Publications by authors named "Francesca Biagioni"

116 Publications

The Role of Cellular Prion Protein in Promoting Stemness and Differentiation in Cancer.

Cancers (Basel) 2021 Jan 6;13(2). Epub 2021 Jan 6.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

Cellular prion protein (PrP) is seminal to modulate a variety of baseline cell functions to grant homeostasis. The classic role of such a protein was defined as a chaperone-like molecule being able to rescue cell survival. Nonetheless, PrP also represents the precursor of the deleterious misfolded variant known as scrapie prion protein (PrP). This variant is detrimental in a variety of prion disorders. This multi-faceted role of PrP is greatly increased by recent findings showing how PrP in its folded conformation may foster tumor progression by acting at multiple levels. The present review focuses on such a cancer-promoting effect. The manuscript analyzes recent findings on the occurrence of PrP in various cancers and discusses the multiple effects, which sustain cancer progression. Within this frame, the effects of PrP on stemness and differentiation are discussed. A special emphasis is provided on the spreading of PrP and the epigenetic effects, which are induced in neighboring cells to activate cancer-related genes. These detrimental effects are further discussed in relation to the aberrancy of its physiological and beneficial role on cell homeostasis. A specific paragraph is dedicated to the role of PrP beyond its effects in the biology of cancer to represent a potential biomarker in the follow up of patients following surgical resection.
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http://dx.doi.org/10.3390/cancers13020170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825291PMC
January 2021

Locus Coeruleus Modulates Neuroinflammation in Parkinsonism and Dementia.

Int J Mol Sci 2020 Nov 16;21(22). Epub 2020 Nov 16.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

Locus Coeruleus (LC) is the main noradrenergic nucleus of the central nervous system, and its neurons widely innervate the whole brain. LC is severely degenerated both in Alzheimer's disease (AD) and in Parkinson's disease (PD), years before the onset of clinical symptoms, through mechanisms that differ among the two disorders. Several experimental studies have shown that noradrenaline modulates neuroinflammation, mainly by acting on microglia/astrocytes function. In the present review, after a brief introduction on the anatomy and physiology of LC, we provide an overview of experimental data supporting a pathogenetic role of LC degeneration in AD and PD. Then, we describe in detail experimental data, obtained in vitro and in vivo in animal models, which support a potential role of neuroinflammation in such a link, and the specific molecules (i.e., released cytokines, glial receptors, including pattern recognition receptors and others) whose expression is altered by LC degeneration and might play a key role in AD/PD pathogenesis. New imaging and biochemical tools have recently been developed in humans to estimate in vivo the integrity of LC, the degree of neuroinflammation, and pathology AD/PD biomarkers; it is auspicable that these will allow in the near future to test the existence of a link between LC-neuroinflammation and neurodegeneration directly in patients.
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http://dx.doi.org/10.3390/ijms21228630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697920PMC
November 2020

Chronic MPTP in Mice Damage-specific Neuronal Phenotypes within Dorsal Laminae of the Spinal Cord.

Neurotox Res 2021 Apr 18;39(2):156-169. Epub 2020 Nov 18.

I.R.C.C.S. Neuromed, via dell'Elettronica, Pozzilli, Italy.

The neurotoxin 1-methyl, 4-phenyl, 1, 2, 3, 6-tetrahydropiridine (MPTP) is widely used to produce experimental parkinsonism. Such a disease is characterized by neuronal damage in multiple regions beyond the nigrostriatal pathway including the spinal cord. The neurotoxin MPTP damages spinal motor neurons. So far, in Parkinson's disease (PD) patients alpha-synuclein aggregates are described in the dorsal horn of the spinal cord. Nonetheless, no experimental investigation was carried out to document whether MPTP affects the sensory compartment of the spinal cord. Thus, in the present study, we investigated whether chronic exposure to small doses of MPTP (5 mg/kg/X2, daily, for 21 days) produces any pathological effect within dorsal spinal cord. This mild neurotoxic protocol produces a damage only to nigrostriatal dopamine (DA) axon terminals with no decrease in DA nigral neurons assessed by quantitative stereology. In these experimental conditions we documented a decrease in enkephalin-, calretinin-, calbindin D28K-, and parvalbumin-positive neurons within lamina I and II and the outer lamina III. Met-Enkephalin and substance P positive fibers are reduced in laminae I and II of chronically MPTP-treated mice. In contrast, as reported in PD patients, alpha-synuclein is markedly increased within spared neurons and fibers of lamina I and II after MPTP exposure. This is the first evidence that experimental parkinsonism produces the loss of specific neurons of the dorsal spinal cord, which are likely to be involved in sensory transmission and in pain modulation providing an experimental correlate for sensory and pain alterations in PD.
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http://dx.doi.org/10.1007/s12640-020-00313-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936970PMC
April 2021

Cell Clearing Systems as Targets of Polyphenols in Viral Infections: Potential Implications for COVID-19 Pathogenesis.

Antioxidants (Basel) 2020 Nov 10;9(11). Epub 2020 Nov 10.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

The novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has generated the ongoing coronavirus disease-2019 (COVID-19) pandemic, still with an uncertain outcome. Besides pneumonia and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), other features became evident in the context of COVID-19. These includes endothelial and coagulation dysfunction with disseminated intravascular coagulation (DIC), and multiple organ dysfunction syndrome (MODS), along with the occurrence of neurological alterations. The multi-system nature of such viral infection is a witness to the exploitation and impairment of ubiquitous subcellular and metabolic pathways for the sake of its life-cycle, ranging from host cell invasion, replication, transmission, up to a cytopathic effect and overt systemic inflammation. In this frame, alterations in cell-clearing systems of the host are emerging as a hallmark in the pathogenesis of various respiratory viruses, including SARS-CoV-2. Indeed, exploitation of the autophagy and proteasome pathways might contribute not only to the replication of the virus at the site of infection but also to the spreading of either mature virions or inflammatory mediators at both cellular and multisystem levels. In this frame, besides a pharmacological therapy, many researchers are wondering if some non-pharmacological substances might counteract or positively modulate the course of the infection. The pharmacological properties of natural compounds have gained increasing attention in the field of alternative and adjunct therapeutic approaches to several diseases. In particular, several naturally-occurring herbal compounds (mostly polyphenols) are reported to produce widespread antiviral, anti-inflammatory, and anti-oxidant effects while acting as autophagy and (immuno)-proteasome modulators. This article attempts to bridge the perturbation of autophagy and proteasome pathways with the potentially beneficial effects of specific phytochemicals and flavonoids in viral infections, with a focus on the multisystem SARS-CoV-2 infection.
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http://dx.doi.org/10.3390/antiox9111105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697279PMC
November 2020

Autophagy-Based Hypothesis on the Role of Brain Catecholamine Response During Stress.

Front Psychiatry 2020 17;11:569248. Epub 2020 Sep 17.

IRCCS Neuromed, Pozzilli, Italy.

Stressful events, similar to abused drugs, significantly affect the homeostatic balance of the catecholamine brain systems while activating compensation mechanisms to restore balance. In detail, norepinephrine (NE)- and dopamine (DA)-containing neurons within the locus coeruleus (LC) and ventral tegmental area (VTA), are readily and similarly activated by psychostimulants and stressful events involving neural processes related to perception, reward, cognitive evaluation, appraisal, and stress-dependent hormonal factors. Brain catecholamine response to stress results in time-dependent regulatory processes involving mesocorticolimbic circuits and networks, where LC-NE neurons respond more readily than VTA-DA neurons. LC-NE projections are dominant in controlling the forebrain DA-targeted areas, such as the nucleus accumbens (NAc) and medial pre-frontal cortex (mPFC). Heavy and persistent coping demand could lead to sustained LC-NE and VTA-DA neuronal activity, that, when persisting chronically, is supposed to alter LC-VTA synaptic connections. Increasing evidence has been provided indicating a role of autophagy in modulating DA neurotransmission and synaptic plasticity. This alters behavior, and emotional/cognitive experience in response to drug abuse and occasionally, to psychological stress. Thus, relevant information to address the role of stress and autophagy can be drawn from psychostimulants research. In the present mini-review we discuss the role of autophagy in brain catecholamine response to stress and its dysregulation. The findings here discussed suggest a crucial role of regulated autophagy in the response and adaptation of LC-NE and VTA-DA systems to stress.
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http://dx.doi.org/10.3389/fpsyt.2020.569248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527533PMC
September 2020

Merging the Multi-Target Effects of Phytochemicals in Neurodegeneration: From Oxidative Stress to Protein Aggregation and Inflammation.

Antioxidants (Basel) 2020 Oct 20;9(10). Epub 2020 Oct 20.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

Wide experimental evidence has been provided in the last decade concerning the neuroprotective effects of phytochemicals in a variety of neurodegenerative disorders. Generally, the neuroprotective effects of bioactive compounds belonging to different phytochemical classes are attributed to antioxidant, anti-aggregation, and anti-inflammatory activity along with the restoration of mitochondrial homeostasis and targeting alterations of cell-clearing systems. Far from being independent, these multi-target effects represent interconnected events that are commonly implicated in the pathogenesis of most neurodegenerative diseases, independently of etiology, nosography, and the specific misfolded proteins being involved. Nonetheless, the increasing amount of data applying to a variety of neurodegenerative disorders joined with the multiple effects exerted by the wide variety of plant-derived neuroprotective agents may rather confound the reader. The present review is an attempt to provide a general guideline about the most relevant mechanisms through which naturally occurring agents may counteract neurodegeneration. With such an aim, we focus on some popular phytochemical classes and bioactive compounds as representative examples to design a sort of main highway aimed at deciphering the most relevant protective mechanisms which make phytochemicals potentially useful in counteracting neurodegeneration. In this frame, we emphasize the potential role of the cell-clearing machinery as a kernel in the antioxidant, anti-aggregation, anti-inflammatory, and mitochondrial protecting effects of phytochemicals.
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http://dx.doi.org/10.3390/antiox9101022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589770PMC
October 2020

The Multi-Faceted Effect of Curcumin in Glioblastoma from Rescuing Cell Clearance to Autophagy-Independent Effects.

Molecules 2020 Oct 20;25(20). Epub 2020 Oct 20.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

The present review focuses on the multi-faceted effects of curcumin on the neurobiology glioblastoma multiforme (GBM), with a special emphasis on autophagy (ATG)-dependent molecular pathways activated by such a natural polyphenol. This is consistent with the effects of curcumin in a variety of experimental models of neurodegeneration, where the molecular events partially overlap with GBM. In fact, curcumin broadly affects various signaling pathways, which are similarly affected in cell degeneration and cell differentiation. The antitumoral effects of curcumin include growth inhibition, cell cycle arrest, anti-migration and anti-invasion, as well as chemo- and radio-sensitizing activity. Remarkably, most of these effects rely on mammalian target of rapamycin (mTOR)-dependent ATG induction. In addition, curcumin targets undifferentiated and highly tumorigenic GBM cancer stem cells (GSCs). When rescuing ATG with curcumin, the tumorigenic feature of GSCs is suppressed, thus counteracting GBM establishment and growth. It is noteworthy that targeting GSCs may also help overcome therapeutic resistance and reduce tumor relapse, which may lead to a significant improvement of GBM prognosis. The present review focuses on the multi-faceted effects of curcumin on GBM neurobiology, which represents an extension to its neuroprotective efficacy.
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http://dx.doi.org/10.3390/molecules25204839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587955PMC
October 2020

mTOR Modulates Intercellular Signals for Enlargement and Infiltration in Glioblastoma Multiforme.

Cancers (Basel) 2020 Sep 2;12(9). Epub 2020 Sep 2.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

Recently, exosomal release has been related to the acquisition of a malignant phenotype in glioblastoma cancer stem cells (GSCs). Remarkably, intriguing reports demonstrate that GSC-derived extracellular vesicles (EVs) contribute to glioblastoma multiforme (GBM) tumorigenesis via multiple pathways by regulating tumor growth, infiltration, and immune invasion. In fact, GSCs release tumor-promoting macrovesicles that can disseminate as paracrine factors to induce phenotypic alterations in glioma-associated parenchymal cells. In this way, GBM can actively recruit different stromal cells, which, in turn, may participate in tumor microenvironment (TME) remodeling and, thus, alter tumor progression. Vice versa, parenchymal cells can transfer their protein and genetic contents to GSCs by EVs; thus, promoting GSCs tumorigenicity. Moreover, GBM was shown to hijack EV-mediated cell-to-cell communication for self-maintenance. The present review examines the role of the mammalian Target of Rapamycin (mTOR) pathway in altering EVs/exosome-based cell-to-cell communication, thus modulating GBM infiltration and volume growth. In fact, exosomes have been implicated in GSC niche maintenance trough the modulation of GSCs stem cell-like properties, thus, affecting GBM infiltration and relapse. The present manuscript will focus on how EVs, and mostly exosomes, may act on GSCs and neighbor non tumorigenic stromal cells to modify their expression and translational profile, while making the TME surrounding the GSC niche more favorable for GBM growth and infiltration. Novel insights into the mTOR-dependent mechanisms regulating EV-mediated intercellular communication within GBM TME hold promising directions for future therapeutic applications.
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http://dx.doi.org/10.3390/cancers12092486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564864PMC
September 2020

BMP-2 Signaling and Mechanotransduction Synergize to Drive Osteogenic Differentiation via YAP/TAZ.

Adv Sci (Weinh) 2020 Aug 16;7(15):1902931. Epub 2020 Jun 16.

Department of Cellular Biophysics Max Planck Institute for Medical Research Jahnstraße 29 Heidelberg 69120 Germany.

Growth factors and mechanical cues synergistically affect cellular functions, triggering a variety of signaling pathways. The molecular levels of such cooperative interactions are not fully understood. Due to its role in osteogenesis, the growth factor bone morphogenetic protein 2 (BMP-2) is of tremendous interest for bone regenerative medicine, osteoporosis therapeutics, and beyond. Here, contribution of BMP-2 signaling and extracellular mechanical cues to the osteogenic commitment of C2C12 cells is investigated. It is revealed that these two distinct pathways are integrated at the transcriptional level to provide multifactorial control of cell differentiation. The activation of osteogenic genes requires the cooperation of BMP-2 pathway-associated Smad1/5/8 heteromeric complexes and mechanosensitive YAP/TAZ translocation. It is further demonstrated that the Smad complexes remain bound onto and active on target genes, even after BMP-2 removal, suggesting that they act as a "molecular memory unit." Thus, synergistic stimulation with BMP-2 and mechanical cues drives osteogenic differentiation in a programmable fashion.
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http://dx.doi.org/10.1002/advs.201902931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404154PMC
August 2020

A Re-Appraisal of Pathogenic Mechanisms Bridging Wet and Dry Age-Related Macular Degeneration Leads to Reconsider a Role for Phytochemicals.

Int J Mol Sci 2020 Aug 3;21(15). Epub 2020 Aug 3.

I.R.C.C.S. Neuromed, Via Atinense, 18, 86077 Pozzilli, Italy.

Which pathogenic mechanisms underlie age-related macular degeneration (AMD)? Are they different for dry and wet variants, or do they stem from common metabolic alterations? Where shall we look for altered metabolism? Is it the inner choroid, or is it rather the choroid-retinal border? Again, since cell-clearing pathways are crucial to degrade altered proteins, which metabolic system is likely to be the most implicated, and in which cell type? Here we describe the unique clearing activity of the retinal pigment epithelium (RPE) and the relevant role of its autophagy machinery in removing altered debris, thus centering the RPE in the pathogenesis of AMD. The cell-clearing systems within the RPE may act as a kernel to regulate the redox homeostasis and the traffic of multiple proteins and organelles toward either the choroid border or the outer segments of photoreceptors. This is expected to cope with the polarity of various domains within RPE cells, with each one owning a specific metabolic activity. A defective clearance machinery may trigger unconventional solutions to avoid intracellular substrates' accumulation through unconventional secretions. These components may be deposited between the RPE and Bruch's membrane, thus generating the drusen, which remains the classic hallmark of AMD. These deposits may rather represent a witness of an abnormal RPE metabolism than a real pathogenic component. The empowerment of cell clearance, antioxidant, anti-inflammatory, and anti-angiogenic activity of the RPE by specific phytochemicals is here discussed.
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http://dx.doi.org/10.3390/ijms21155563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432893PMC
August 2020

Quantitative Ultrastructural Morphometry and Gene Expression of mTOR-Related Mitochondriogenesis within Glioblastoma Cells.

Int J Mol Sci 2020 Jun 27;21(13). Epub 2020 Jun 27.

I.R.C.C.S. Neuromed, via Atinense 18, 86077 Pozzilli (IS), Italy.

In glioblastoma (GBM) cells, an impairment of mitochondrial activity along with autophagy suppression occurs. Autophagy suppression in GBM promotes stemness, invasion, and poor prognosis. The autophagy deficit seems to be due, at least in part, to an abnormal up-regulation of the mammalian target of rapamycin (mTOR), which may be counteracted by pharmacological mTORC1 inhibition. Since autophagy activation is tightly bound to increased mitochondriogenesis, a defect in the synthesis of novel mitochondria is expected to occur in GBM cells. In an effort to measure a baseline deficit in mitochondria and promote mitochondriogenesis, the present study used two different GBM cell lines, both featuring mTOR hyperactivity. mTORC1 inhibition increases the expression of genes and proteins related to autophagy, mitophagy, and mitochondriogenesis. Autophagy activation was counted by RT-PCR of autophagy genes, LC3- immune-fluorescent puncta and immune-gold, as well as specific mitophagy-dependent BNIP3 stoichiometric increase in situ, within mitochondria. The activation of autophagy-related molecules and organelles after rapamycin exposure occurs concomitantly with progression of autophagosomes towards lysosomes. Remarkably, mitochondrial biogenesis and plasticity (increased mitochondrial number, integrity, and density as well as decreased mitochondrial area) was long- lasting for weeks following rapamycin withdrawal.
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http://dx.doi.org/10.3390/ijms21134570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370179PMC
June 2020

A novel POLR3A genotype leads to leukodystrophy type-7 in two siblings with unusually late age of onset.

BMC Neurol 2020 Jun 29;20(1):258. Epub 2020 Jun 29.

I.R.C.C.S. I.N.M. Neuromed, via Atinense 18, 86077, Pozzilli, Italy.

Background: Leukodystrophies are familial heterogeneous disorders primarily affecting the white matter, which are defined as hypomyelinating or demyelinating based on disease severity as assessed at MRI. Recently, a group of clinically overlapping hypomyelinating leukodystrophies (HL) has been associated with mutations in RNA polymerase III enzymes (Pol III) subunits.

Case Presentation: In this manuscript, we describe two Italian siblings carrying a novel POLR3A genotype. MRI imaging, genetic analysis, and clinical data led to diagnosing HL type 7. The female sibling, at the age of 34, is tetra-paretic and suffers from severe cognitive regression. She had a disease onset at the age of 19, characterized by slow and progressive cognitive impairment associated with gait disturbances and amenorrhea. The male sibling was diagnosed during an MRI carried out for cephalalgia at the age of 41. After 5 years, he developed mild cognitive impairment, dystonia with 4-limb hypotonia, and moderate dysmetria with balance and gait impairment.

Conclusions: The present study provides the first evidence of unusually late age of onset in HL, describing two siblings with a novel POLR3A genotype which showed the first symptoms at the age of 41 and 19, respectively. This provides a powerful insight into clinical heterogeneity and genotype-phenotype correlation in POLR3A related HL.
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http://dx.doi.org/10.1186/s12883-020-01835-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322863PMC
June 2020

Cell-Clearing Systems Bridging Repeat Expansion Proteotoxicity and Neuromuscular Junction Alterations in ALS and SBMA.

Int J Mol Sci 2020 Jun 4;21(11). Epub 2020 Jun 4.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

The coordinated activities of autophagy and the ubiquitin proteasome system (UPS) are key to preventing the aggregation and toxicity of misfold-prone proteins which manifest in a number of neurodegenerative disorders. These include proteins which are encoded by genes containing nucleotide repeat expansions. In the present review we focus on the overlapping role of autophagy and the UPS in repeat expansion proteotoxicity associated with chromosome 9 open reading frame 72 () and androgen receptor () genes, which are implicated in two motor neuron disorders, amyotrophic lateral sclerosis (ALS) and spinal-bulbar muscular atrophy (SBMA), respectively. At baseline, both C9ORF72 and AR regulate autophagy, while their aberrantly-expanded isoforms may lead to a failure in both autophagy and the UPS, further promoting protein aggregation and toxicity within motor neurons and skeletal muscles. Besides proteotoxicity, autophagy and UPS alterations are also implicated in neuromuscular junction (NMJ) alterations, which occur early in both ALS and SBMA. In fact, autophagy and the UPS intermingle with endocytic/secretory pathways to regulate axonal homeostasis and neurotransmission by interacting with key proteins which operate at the NMJ, such as agrin, acetylcholine receptors (AChRs), and adrenergic beta2 receptors (B2-ARs). Thus, alterations of autophagy and the UPS configure as a common hallmark in both ALS and SBMA disease progression. The findings here discussed may contribute to disclosing overlapping molecular mechanisms which are associated with a failure in cell-clearing systems in ALS and SBMA.
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http://dx.doi.org/10.3390/ijms21114021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312203PMC
June 2020

Epilepsy and Alzheimer's Disease: Potential mechanisms for an association.

Brain Res Bull 2020 07 5;160:107-120. Epub 2020 May 5.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; I.R.C.C.S. I.N.M. Neuromed, Pozzilli, Italy. Electronic address:

Alzheimer's Disease (AD) and epilepsy are common neurological diseases. The prevalence of epilepsy in AD patients is higher than in healthy subjects, but identifying the reasons for this association, the characteristics of seizures in AD, and the implications for prognosis and treatment is challenging. The present review provides first of all an overview of the main clinical aspects of AD and epilepsy, of their reciprocal relationship, and of the challenges that identifying seizures in AD patients presents. Limitations of clinical studies addressing this topic are discussed, including their mostly prospective nature and possible selection biases. A comprehensive, mechanistic discussion on the factors that are most likely to underlie the increased risk for seizures in AD follows. These include, for instance, GABAergic and glutamatergic alterations, Aβ and Tau protein, the role of the noradrenergic nucleus Locus Coeruleus, and neuroinflammation. Finally, evidence concerning the role that epilepsy may have in exacerbating or initiating AD is reviewed. A mechanistic insight on the relationship between epilepsy and AD might have relevant implications for improving the treatment of AD patients, as well as in elucidating pathophysiological mechanisms.
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http://dx.doi.org/10.1016/j.brainresbull.2020.04.009DOI Listing
July 2020

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies.

Int J Mol Sci 2020 Apr 24;21(8). Epub 2020 Apr 24.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

Alterations in autophagy and the ubiquitin proteasome system (UPS) are commonly implicated in protein aggregation and toxicity which manifest in a number of neurological disorders. In fact, both UPS and autophagy alterations are bound to the aggregation, spreading and toxicity of the so-called prionoid proteins, including alpha synuclein (α-syn), amyloid-beta (Aβ), tau, huntingtin, superoxide dismutase-1 (SOD-1), TAR-DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS). Recent biochemical and morphological studies add to this scenario, focusing on the coordinated, either synergistic or compensatory, interplay that occurs between autophagy and the UPS. In fact, a number of biochemical pathways such as mammalian target of rapamycin (mTOR), transcription factor EB (TFEB), Bcl2-associated athanogene 1/3 (BAG3/1) and glycogen synthase kinase beta (GSk3β), which are widely explored as potential targets in neurodegenerative proteinopathies, operate at the crossroad between autophagy and UPS. These biochemical steps are key in orchestrating the specificity and magnitude of the two degradation systems for effective protein homeostasis, while intermingling with intracellular secretory/trafficking and inflammatory pathways. The findings discussed in the present manuscript are supposed to add novel viewpoints which may further enrich our insight on the complex interactions occurring between cell-clearing systems, protein misfolding and propagation. Discovering novel mechanisms enabling a cross-talk between the UPS and autophagy is expected to provide novel potential molecular targets in proteinopathies.
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http://dx.doi.org/10.3390/ijms21083028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215558PMC
April 2020

Potential Antidepressant Effects of Scutellaria baicalensis, Hericium erinaceus and Rhodiola rosea.

Antioxidants (Basel) 2020 Mar 12;9(3). Epub 2020 Mar 12.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126, Pisa, Italy.

Recent studies focused on the pharmacology and feasibility of herbal compounds as a potential strategy to target a variety of human diseases ranging from metabolic to brain disorders. Accordingly, bioactive ingredients which are found within a variety of herbal compounds are reported to produce both neuroprotective and psychotropic activities which may help to combat mental disorders such as depression, anxiety, sleep disturbances and cognitive alterations. In the present manuscript, we focus on three herbs which appear effective in mitigating anxiety or depression with favourable risk-benefit profiles, namely Scutellaria baicalensis (), Hericium erinaceus () and Rhodiola rosea (). These three traditional folk medicinal herbs target the main biochemical events that are implicated in mental disorders, mimicking, to some extent, the mechanisms of action of conventional antidepressants and mood stabilizers with a wide margin of tolerability. In detail, they rescue alterations in neurotransmitter and neuro-endocrine systems, stimulate neurogenesis and the synthesis of neurotrophic factors, and they counteract oxidative stress, mitochondrial dysfunction and inflammation. Albeit the encouraging results that emerge from both experimental and clinical evidence, further studies are needed to confirm and better understand the mental-health promoting, and specifically, the antidepressant effects of these herbs.
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http://dx.doi.org/10.3390/antiox9030234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139475PMC
March 2020

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update.

Int J Mol Sci 2020 Feb 28;21(5). Epub 2020 Feb 28.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

Recent evidence suggests that autophagy impairment is implicated in the epileptogenic mechanisms downstream of mTOR hyperactivation. This holds true for a variety of genetic and acquired epileptic syndromes besides malformations of cortical development which are classically known as mTORopathies. Autophagy suppression is sufficient to induce epilepsy in experimental models, while rescuing autophagy prevents epileptogenesis, improves behavioral alterations, and provides neuroprotection in seizure-induced neuronal damage. The implication of autophagy in epileptogenesis and maturation phenomena related to seizure activity is supported by evidence indicating that autophagy is involved in the molecular mechanisms which are implicated in epilepsy. In general, mTOR-dependent autophagy regulates the proliferation and migration of inter-/neuronal cortical progenitors, synapse development, vesicular release, synaptic plasticity, and importantly, synaptic clustering of GABA receptors and subsequent excitatory/inhibitory balance in the brain. Similar to autophagy, the ubiquitin-proteasome system is regulated downstream of mTOR, and it is implicated in epileptogenesis. Thus, mTOR-dependent cell-clearing systems are now taking center stage in the field of epilepsy. In the present review, we discuss such evidence in a variety of seizure-related disorders and models. This is expected to provide a deeper insight into the molecular mechanisms underlying seizure activity.
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http://dx.doi.org/10.3390/ijms21051642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084443PMC
February 2020

A Novel Homozygous Variant in the Fork-Head-Associated Domain of Polynucleotide Kinase Phosphatase in a Patient Affected by Late-Onset Ataxia With Oculomotor Apraxia Type 4.

Front Neurol 2019 15;10:1331. Epub 2020 Jan 15.

IRCCS Neuromed, Pozzilli, Italy.

Ataxia with oculomotor apraxia (AOA) is a clinical syndrome featuring a group of genetic diseases including at least four separate autosomal-recessive cerebellar ataxias. All these disorders are due to altered genes involved in DNA repair. AOA type 4 (AOA4) is caused by mutations in DNA repair factor polynucleotide kinase phosphatase (, which encodes for a DNA processing enzyme also involved in other syndromes featured by microcephaly or neurodegeneration. To date, only a few AOA4 patients have been reported worldwide. All these patients are homozygous or compound heterozygous carriers for mutations in the kinase domain of . In this report, we describe a 56 years old patient affected by AOA4 characterized by ataxia, polyneuropathy, oculomotor apraxia, and cognitive impairment with the absence of dystonia. The disease is characterized by a very late onset (50 years) when compared with other AOA4 patients described so far (median age of onset at 4 years). In this proband, Clinical Exome Analysis through Next Generation Sequencing (NGS) consisting of 4,800 genes, identified the homozygous mutation p.Gln50Glu. This variant, classified as a likely pathogenic variant according to American College of Medical Genetics (ACMG) guidelines, does not involve the kinase domain but falls in the fork-head-associated (FHA) domain. So far, mutations in such a domain were reported to associate only with a pure seizure syndrome without the classic AOA4 features. Therefore, this is the first report of patients carrying a mutation of the FHA domain within the gene which expresses the clinical phenotype known as the AOA4 syndrome and the lack of any seizure activity. Further studies are required to investigate specifically the significance of various mutations within the FHA domain, and it would be worth to correlate these variants with the age of onset of the AOA4 syndrome.
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http://dx.doi.org/10.3389/fneur.2019.01331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974581PMC
January 2020

Dissecting Molecular Features of Gliomas: Genetic Loci and Validated Biomarkers.

Int J Mol Sci 2020 Jan 20;21(2). Epub 2020 Jan 20.

IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli, Italy.

Recently, several studies focused on the genetics of gliomas. This allowed identifying several germline loci that contribute to individual risk for tumor development, as well as various somatic mutations that are key for disease classification. Unfortunately, none of the germline loci clearly confers increased risk per se. Contrariwise, somatic mutations identified within the glioma tissue define tumor genotype, thus representing valid diagnostic and prognostic markers. Thus, genetic features can be used in glioma classification and guided therapy. Such copious genomic variabilities are screened routinely in glioma diagnosis. In detail, Sanger sequencing or pyrosequencing, fluorescence in-situ hybridization, and microsatellite analyses were added to immunohistochemistry as diagnostic markers. Recently, Next Generation Sequencing was set-up as an all-in-one diagnostic tool aimed at detecting both DNA copy number variations and mutations in gliomas. This approach is widely used also to detect circulating tumor DNA within cerebrospinal fluid from patients affected by primary brain tumors. Such an approach is providing an alternative cost-effective strategy to genotype all gliomas, which allows avoiding surgical tissue collection and repeated tumor biopsies. This review summarizes available molecular features that represent solid tools for the genetic diagnosis of gliomas at present or in the next future.
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http://dx.doi.org/10.3390/ijms21020685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014190PMC
January 2020

Cooperation Between MYC and β-Catenin in Liver Tumorigenesis Requires Yap/Taz.

Hepatology 2020 10 29;72(4):1430-1443. Epub 2020 Jul 29.

European Institute of Oncology (IEO)-IRCCS, Milan, Italy.

Background And Aims: Activation of MYC and catenin beta-1 (CTNNB1, encoding β-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear.

Approach And Results: We generated a mouse model allowing conditional activation of MYC and WNT/β-catenin signaling (through either β-catenin activation or loss of APC - adenomatous polyposis coli) upon expression of CRE recombinase in the liver and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles, and tumorigenesis. Activation of WNT/β-catenin signaling strongly accelerated MYC-driven carcinogenesis in the liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and β-catenin in hepatocytes, followed by RNA-sequencing profiling, allowed the identification of a "Myc/β-catenin signature," composed of a discrete set of Myc-activated genes whose expression increased in the presence of active β-catenin. Notably, this signature enriched for targets of Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz), two transcriptional coactivators known to be activated by WNT/β-catenin signaling and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/β-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/β-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis.

Conclusions: Myc and β-catenin show a strong cooperative action in liver carcinogenesis, with Yap and Taz serving as mediators of this effect. These findings warrant efforts toward therapeutic targeting of Yap/Taz in aggressive liver tumors marked by elevated Myc/β-catenin activity.
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http://dx.doi.org/10.1002/hep.31120DOI Listing
October 2020

Motor Neurons Pathology After Chronic Exposure to MPTP in Mice.

Neurotox Res 2020 Feb 13;37(2):298-313. Epub 2019 Nov 13.

I.R.C.C.S. Neuromed, Via Atinense, 18, Pozzilli, Italy.

The neurotoxin 1-methyl,4-phenyl-1,2,3,6-tetrahydropiridine (MPTP) is widely used to produce experimental parkinsonism in rodents and primates. Among different administration protocols, continuous or chronic exposure to small amounts of MPTP is reported to better mimic cell pathology reminiscent of Parkinson's disease (PD). Catecholamine neurons are the most sensitive to MPTP neurotoxicity; however, recent studies have found that MPTP alters the fine anatomy of the spinal cord including motor neurons, thus overlapping again with the spinal cord involvement documented in PD. In the present study, we demonstrate that chronic exposure to low amounts of MPTP (10 mg/kg daily, × 21 days) significantly reduces motor neurons in the ventral lumbar spinal cord while increasing α-synuclein immune-staining within the ventral horn. Spinal cord involvement in MPTP-treated mice extends to Calbindin D28 KDa immune-reactive neurons other than motor neurons within lamina VII. These results were obtained in the absence of significant reduction of dopaminergic cell bodies in the Substantia Nigra pars compacta, while a slight decrease was documented in striatal tyrosine hydroxylase immune-staining. Thus, the present study highlights neuropathological similarities between dopaminergic neurons and spinal motor neurons and supports the pathological involvement of spinal cord in PD and experimental MPTP-induced parkinsonism. Remarkably, the toxic threshold for motor neurons appears to be lower compared with nigral dopaminergic neurons following a chronic pattern of MPTP intoxication. This sharply contrasts with previous studies showing that MPTP intoxication produces comparable neuronal loss within spinal cord and Substantia Nigra.
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http://dx.doi.org/10.1007/s12640-019-00121-yDOI Listing
February 2020

Molecular Mechanisms Linking ALS/FTD and Psychiatric Disorders, the Potential Effects of Lithium.

Front Cell Neurosci 2019 4;13:450. Epub 2019 Oct 4.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.

Altered proteostasis, endoplasmic reticulum (ER) stress, abnormal unfolded protein response (UPR), mitochondrial dysfunction and autophagy impairment are interconnected events, which contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). In recent years, the mood stabilizer lithium was shown to potentially modify ALS/FTD beyond mood disorder-related pathology. The effects of lithium are significant in ALS patients carrying genetic variations in the UNC13 presynaptic protein, which occur in ALS/FTD and psychiatric disorders as well. In the brain, lithium modulates a number of biochemical pathways involved in synaptic plasticity, proteostasis, and neuronal survival. By targeting UPR-related events, namely ER stress, excitotoxicity and autophagy dysfunction, lithium produces plastic effects. These are likely to relate to neuroprotection, which was postulated for mood and motor neuron disorders. In the present manuscript, we try to identify and discuss potential mechanisms through which lithium copes concomitantly with ER stress, UPR and autophagy dysfunctions related to UNC13 synaptic alterations and aberrant RNA and protein processing. This may serve as a paradigm to provide novel insights into the neurobiology of ALS/FTD featuring early psychiatric disturbances.
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http://dx.doi.org/10.3389/fncel.2019.00450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797817PMC
October 2019

Prion Protein in Glioblastoma Multiforme.

Int J Mol Sci 2019 Oct 15;20(20). Epub 2019 Oct 15.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126 Pisa, Italy.

The cellular prion protein (PrPc) is an evolutionarily conserved cell surface protein encoded by the gene. PrPc is ubiquitously expressed within nearly all mammalian cells, though most abundantly within the CNS. Besides being implicated in the pathogenesis and transmission of prion diseases, recent studies have demonstrated that PrPc contributes to tumorigenesis by regulating tumor growth, differentiation, and resistance to conventional therapies. In particular, PrPc over-expression has been related to the acquisition of a malignant phenotype of cancer stem cells (CSCs) in a variety of solid tumors, encompassing pancreatic ductal adenocarcinoma (PDAC), osteosarcoma, breast cancer, gastric cancer, and primary brain tumors, mostly glioblastoma multiforme (GBM). Thus, PrPc is emerging as a key in maintaining glioblastoma cancer stem cells' (GSCs) phenotype, thereby strongly affecting GBM infiltration and relapse. In fact, PrPc contributes to GSCs niche's maintenance by modulating GSCs' stem cell-like properties while restraining them from differentiation. This is the first review that discusses the role of PrPc in GBM. The manuscript focuses on how PrPc may act on GSCs to modify their expression and translational profile while making the micro-environment surrounding the GSCs niche more favorable to GBM growth and infiltration.
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http://dx.doi.org/10.3390/ijms20205107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834196PMC
October 2019

TREM Receptors Connecting Bowel Inflammation to Neurodegenerative Disorders.

Cells 2019 09 21;8(10). Epub 2019 Sep 21.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56100 Pisa, Italy.

Alterations in Triggering Receptors Expressed on Myeloid cells (TREM-1/2) are bound to a variety of infectious, sterile inflammatory, and degenerative conditions, ranging from inflammatory bowel disease (IBD) to neurodegenerative disorders. TREMs are emerging as key players in pivotal mechanisms often concurring in IBD and neurodegeneration, namely microbiota dysbiosis, leaky gut, and inflammation. In conditions of dysbiosis, compounds released by intestinal bacteria activate TREMs on macrophages, leading to an exuberant pro-inflammatory reaction up to damage in the gut barrier. In turn, TREM-positive activated macrophages along with inflammatory mediators may reach the brain through the blood, glymphatic system, circumventricular organs, or the vagus nerve via the microbiota-gut-brain axis. This leads to a systemic inflammatory response which, in turn, impairs the blood-brain barrier, while promoting further TREM-dependent neuroinflammation and, ultimately, neural injury. Nonetheless, controversial results still exist on the role of TREM-2 compared with TREM-1, depending on disease specificity, stage, and degree of inflammation. Therefore, the present review aimed to provide an update on the role of TREMs in the pathophysiology of IBD and neurodegeneration. The evidence here discussed the highlights of the potential role of TREMs, especially TREM-1, in bridging inflammatory processes in intestinal and neurodegenerative disorders.
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http://dx.doi.org/10.3390/cells8101124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829526PMC
September 2019

The role of Locus Coeruleus in neuroinflammation occurring in Alzheimer's disease.

Brain Res Bull 2019 11 13;153:47-58. Epub 2019 Aug 13.

I.R.C.C.S. I.N.M. Neuromed, Pozzilli, Italy; Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. Electronic address:

Alzheimer's Disease (AD) represents the main degenerative dementia. Its neuropathological hallmarks are β-amyloid plaques (APs) and neurofibrillary tangles (NFT), which lead to neuronal loss and brain atrophy. Recent data show that, early in the course of AD, hyperphosphorylated Tau proteins accumulate in Locus Coeruleus (LC) neuronal bodies. The fact that similar alterations have been found also in the entorhinal cortex suggests a causal relationship, although no final causal evidence exists. Later on, in the course of the disease, frank LC neuronal loss occurs, which is associated with marked cerebral NE reduction. In AD, neuroinflammation plays a pivotal role early in the process of APs deposition. LC degeneration is likely to play a key role in AD pathogenesis. In fact, NE modulates growth factors expression as well as integrity and functioning of the blood-brain barrier, and it also directly affects neuroinflammation. For instance, LC modulates microglia and astrocyte function, and this is evident following damage to LC, which induces astro- and micro-gliosis around APs, as well as interleukins secretion. These phenomena are dependent on the activation of beta-adrenergic receptors. The present review provides evidence about immune-mediated mechanisms through which LC may impact the course of AD. Some findings are consolidated in animal models. Should these data be confirmed in humans, adrenergic agents might represent potential therapeutic approaches acting on neuroinflammation to slow down the progression of AD.
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http://dx.doi.org/10.1016/j.brainresbull.2019.08.007DOI Listing
November 2019

The Autophagy Status of Cancer Stem Cells in Gliobastoma Multiforme: From Cancer Promotion to Therapeutic Strategies.

Int J Mol Sci 2019 Aug 5;20(15). Epub 2019 Aug 5.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126, Pisa, Italy.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor featuring rapid cell proliferation, treatment resistance, and tumor relapse. This is largely due to the coexistence of heterogeneous tumor cell populations with different grades of differentiation, and in particular, to a small subset of tumor cells displaying stem cell-like properties. This is the case of glioma stem cells (GSCs), which possess a powerful self-renewal capacity, low differentiation, along with radio- and chemo-resistance. Molecular pathways that contribute to GBM stemness of GSCs include mTOR, Notch, Hedgehog, and Wnt/β-catenin. Remarkably, among the common biochemical effects that arise from alterations in these pathways, autophagy suppression may be key in promoting GSCs self-renewal, proliferation, and pluripotency maintenance. In fact, besides being a well-known downstream event of mTOR hyper-activation, autophagy downregulation is also bound to the effects of aberrantly activated Notch, Hedgehog, and Wnt/β-catenin pathways in GBM. As a major orchestrator of protein degradation and turnover, autophagy modulates proliferation and differentiation of normal neuronal stem cells (NSCs) as well as NSCs niche maintenance, while its failure may contribute to GSCs expansion and maintenance. Thus, in the present review we discuss the role of autophagy in GSCs metabolism and phenotype in relationship with dysregulations of a variety of NSCs controlling pathways, which may provide novel insights into GBM neurobiology.
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http://dx.doi.org/10.3390/ijms20153824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695733PMC
August 2019

Phytochemicals Bridging Autophagy Induction and Alpha-Synuclein Degradation in Parkinsonism.

Int J Mol Sci 2019 Jul 3;20(13). Epub 2019 Jul 3.

Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa (PI), Italy.

Among nutraceuticals, phytochemical-rich compounds represent a source of naturally-derived bioactive principles, which are extensively studied for potential beneficial effects in a variety of disorders ranging from cardiovascular and metabolic diseases to cancer and neurodegeneration. In the brain, phytochemicals produce a number of biological effects such as modulation of neurotransmitter activity, growth factor induction, antioxidant and anti-inflammatory activity, stem cell modulation/neurogenesis, regulation of mitochondrial homeostasis, and counteracting protein aggregation through modulation of protein-folding chaperones and the cell clearing systems autophagy and proteasome. In particular, the ability of phytochemicals in restoring proteostasis through autophagy induction took center stage in recent research on neurodegenerative disorders such as Parkinson's disease (PD). Indeed, autophagy dysfunctions and α-syn aggregation represent two interdependent downstream biochemical events, which concur in the parkinsonian brain, and which are targeted by phytochemicals administration. Therefore, in the present review we discuss evidence about the autophagy-based neuroprotective effects of specific phytochemical-rich plants in experimental parkinsonism, with a special focus on their ability to counteract alpha-synuclein aggregation and toxicity. Although further studies are needed to confirm the autophagy-based effects of some phytochemicals in parkinsonism, the evidence discussed here suggests that rescuing autophagy through natural compounds may play a role in preserving dopamine (DA) neuron integrity by counteracting the aggregation, toxicity, and prion-like spreading of α-syn, which remains a hallmark of PD.
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http://dx.doi.org/10.3390/ijms20133274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651086PMC
July 2019

Methamphetamine persistently increases alpha-synuclein and suppresses gene promoter methylation within striatal neurons.

Brain Res 2019 09 28;1719:157-175. Epub 2019 May 28.

I.R.C.C.S. I.N.M. Neuromed, via Atinense 18, 86077 Pozzilli (IS), Italy; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126 Pisa, Italy. Electronic address:

Methamphetamine (Meth) produces a variety of epigenetic effects in the brain, which are seminal to establish long-lasting alterations in neuronal activity. However, most epigenetic changes were described by measuring the rough amount of either histone acetylation and methylation or direct DNA methylation, without focusing on a specific DNA sequence. This point is key to comprehend Meth-induced phenotypic changes, brain plasticity, addiction and neurodegeneration. In this research paper we analyze the persistence of Meth-induced striatal synucleinopathy at a prolonged time interval of Meth withdrawal. At the same time, Meth-induced alterations, specifically within alpha-synuclein gene (SNCA) or its promoter, were evaluated. We found that exposure to high and/or prolonged doses of Meth, apart from producing nigro-striatal toxicity, determines a long-lasting increase in striatal alpha-synuclein levels. This is consistent along immune-blotting, immune-histochemistry, and electron microscopy. This was neither associated with an increase of SNCA copy number nor with alterations within SNCA sequence. However, we documented persistently demethylation within SNCA promoter, which matches the increase in alpha-synuclein protein. The amount of the native protein, which was measured stoichiometrically within striatal neurons, surpasses the increase reported following SNCA multiplications. Demethylation was remarkable (ten-fold of controls) and steady, even at prolonged time intervals being tested so far (up to 21 days of Meth withdrawal). Similarly alpha-synuclein protein assayed stoichiometrically steadily increased roughly ten-fold of controls. Meth-induced increase of alpha-synuclein was also described within limbic areas. These findings are discussed in the light of Meth-induced epigenetic changes, Meth-induced phenotype alterations, and Meth-induced neurodegeneration.
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http://dx.doi.org/10.1016/j.brainres.2019.05.035DOI Listing
September 2019

ccf-mtDNA as a Potential Link Between the Brain and Immune System in Neuro-Immunological Disorders.

Front Immunol 2019 9;10:1064. Epub 2019 May 9.

I.R.C.C.S Neuromed, Via Atinense, Pozzilli, Italy.

Fragments of mitochondrial DNA (mtDNA) are released outside the cell and they appear to persist in extracellular fluids as circulating, cell-free, mtDNA (ccf-mtDNA). When compared to nuclear DNA, such a double stranded mtDNA is more resistant to nuclease degradation. In fact, it is stable extracellularly where it can be detected in both plasma and cerebrospinal fluid (CSF), here acting as a potential biomarker in various disorders. In neurological diseases (Alzheimer's disease, Parkinson's disease and end-stage progressive Multiple Sclerosis), a decreased amount of CSF ccf-mtDNA is related with progressive cell dysfunction. This suggests an alteration in neuronal mtDNA levels (mtDNA replication, degradation and depletion) in vulnerable brain regions at early stages of neurodegeneration leading to reduced mtDNA release, which takes place before actual cell death occurs. On the other hand, elevated CSF ccf-mtDNA levels are reported in acute phases of relapsing-remitting Multiple Sclerosis (RRMS). This occurs during acute inflammation, which anticipates the neurodegenerative process. Thus, an increase in inflammatory cells in the affected regions is expected to add on mtDNA release into the CSF. In addition, similarly to bacterial DNA, the non-methylated CpG sites of mtDNA, which activate innate immunity and inflammation, are likely to participate in the molecular mechanisms of disease. Thus, ccf-mtDNA may represent a powerful biomarker for disease screening and prognosis at early stage, although its biological role may extend to generating the neurobiology of disease. The present manuscript discusses recent experimental findings in relationship with clinical evidence comparing neuro-immunological features of neurodegenerative disorders with frankly neuro-infectious diseases.
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http://dx.doi.org/10.3389/fimmu.2019.01064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520662PMC
June 2020

The Effects of Amphetamine and Methamphetamine on the Release of Norepinephrine, Dopamine and Acetylcholine From the Brainstem Reticular Formation.

Front Neuroanat 2019 10;13:48. Epub 2019 May 10.

Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.

Amphetamine (AMPH) and methamphetamine (METH) are widely abused psychostimulants, which produce a variety of psychomotor, autonomic and neurotoxic effects. The behavioral and neurotoxic effects of both compounds (from now on defined as AMPHs) stem from a fair molecular and anatomical specificity for catecholamine-containing neurons, which are placed in the brainstem reticular formation (RF). In fact, the structural cross-affinity joined with the presence of shared molecular targets between AMPHs and catecholamine provides the basis for a quite selective recruitment of brainstem catecholamine neurons following AMPHs administration. A great amount of investigations, commentary manuscripts and books reported a pivotal role of mesencephalic dopamine (DA)-containing neurons in producing behavioral and neurotoxic effects of AMPHs. Instead, the present review article focuses on catecholamine reticular neurons of the low brainstem. In fact, these nuclei add on DA mesencephalic cells to mediate the effects of AMPHs. Among these, we also include two pontine cholinergic nuclei. Finally, we discuss the conundrum of a mixed neuronal population, which extends from the pons to the periaqueductal gray (PAG). In this way, a number of reticular nuclei beyond classic DA mesencephalic cells are considered to extend the scenario underlying the neurobiology of AMPHs abuse. The mechanistic approach followed here to describe the action of AMPHs within the RF is rooted on the fine anatomy of this region of the brainstem. This is exemplified by a few medullary catecholamine neurons, which play a pivotal role compared with the bulk of peripheral sympathetic neurons in sustaining most of the cardiovascular effects induced by AMPHs.
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http://dx.doi.org/10.3389/fnana.2019.00048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524618PMC
May 2019