Publications by authors named "Tiago Fleming Outeiro"

91 Publications

Emerging concepts in synucleinopathies.

Acta Neuropathol 2021 Feb 24. Epub 2021 Feb 24.

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center, Göttingen, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-021-02290-7DOI Listing
February 2021

Doxycycline inhibits α-synuclein-associated pathologies in vitro and in vivo.

Neurobiol Dis 2021 Apr 8;151:105256. Epub 2021 Jan 8.

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Goettingen, Germany; Max Planck Institute for Experimental Medicine, Goettingen, Germany; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK. Electronic address:

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn). Doxycycline, a tetracyclic antibiotic shows neuroprotective effects, initially proposed to be due to its anti-inflammatory properties. More recently, an additional mechanism by which doxycycline may exert its neuroprotective effects has been proposed as it has been shown that it inhibits amyloid aggregation. Here, we studied the effects of doxycycline on aSyn aggregation in vivo, in vitro and in a cell free system using real-time quaking induced conversion (RT-QuiC). Using H4, SH-SY5Y and HEK293 cells, we found that doxycycline decreases the number and size of aSyn aggregates in cells. In addition, doxycycline inhibits the aggregation and seeding of recombinant aSyn, and attenuates the production of mitochondrial-derived reactive oxygen species. Finally, we found that doxycycline induces a cellular redistribution of aggregates in a C.elegans animal model of PD, an effect that is associated with a recovery of dopaminergic function. In summary, we provide strong evidence that doxycycline treatment may be an effective strategy against synucleinopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2021.105256DOI Listing
April 2021

Alpha-Synuclein Antibody Characterization: Why Semantics Matters.

Mol Neurobiol 2021 Jan 7. Epub 2021 Jan 7.

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center, Göttingen, Germany.

In protein aggregation disorders, we assume that, during the process of protein aggregation, different types of aggregated species (oligomers, protofibrils, fibrils, etc.) are formed, some of which can be toxic to cells/tissues/organs. Recent evidence from numerous studies in cell and animal models of disease suggest that oligomeric species of different proteins might be more toxic that the larger, fibrillar forms. However, we still lack definitive data on the nature of the toxic species, mostly due to our inability to detect and define the various protein species that form as protein aggregate. The terms used are often broad and do not capture inter-laboratory variation in protocols and methods used for the characterization of aggregates. Even antibody-based methods can be ambiguous, as antibodies are delicate tools. Therefore, systematic and interdisciplinary studies are essential in order to guide future developments in the field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12035-020-02269-7DOI Listing
January 2021

JM-20 protects against 6-hydroxydopamine-induced neurotoxicity in models of Parkinson's disease: Mitochondrial protection and antioxidant properties.

Neurotoxicology 2021 01 21;82:89-98. Epub 2020 Nov 21.

Centro de Investigación y Desarrollo de Medicamentos (CIDEM), Ave 26, No. 1605 Boyeros y Puentes Grandes, CP 10600, La Habana, Cuba. Electronic address:

We have previously shown that JM-20, a new chemical entity consisting of 1,5-benzodiazepine fused to a dihydropyridine moiety, protects against rotenone-induced neurotoxicity in an experimental model of Parkinson's disease (PD). The aim of this study was to investigate the effect of a novel hybrid molecule, named JM-20, in in vitro and in vivo models of PD induced by 6-hydroxydopamine (6-OHDA). PC-12 cells were exposed to 6-OHDA and treated with JM-20. Protection against mitochondrial damage induced by 6-OHDA was also investigated using isolated rat brain mitochondria. We found that JM-20 protected PC-12 cells against cytotoxicity induced by 6-OHDA and inhibited hydrogen peroxide generation, mitochondrial swelling and membrane potential dissipation. For in vivo experiments, adult male Wistar rats were lesioned in the substantia nigra pars compacta (SNpc) by 6-OHDA administration. JM-20 was orally administered (10, 20 or 40 mg/kg), intragastric via gavage, 24 h after surgery and daily for seven days. Treatment with JM-20 significantly reduced the percentage of motor asymmetry and increased vertical exploration. It improved the redox state of the SNpc and the striatal tissue of these animals. Also, JM-20 reduced glial fibrillary acidic protein overexpression and increased tyrosine hydroxylase-positive cell number, both in SNpc. Altogether, these results demonstrate that JM-20 is a potential neuroprotective agent against 6-OHDA-induced damage in both in vitro and in vivo models. The mechanism underlying JM-20 neuroprotection against 6-OHDA appears to be associated with the control of oxidative injury and mitochondrial impairment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuro.2020.11.005DOI Listing
January 2021

Pharmacological Modulators of Tau Aggregation and Spreading.

Brain Sci 2020 Nov 13;10(11). Epub 2020 Nov 13.

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, 37073 Goettingen, Germany.

Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates composed of abnormal tau protein in the brain. Additionally, misfolded forms of tau can propagate from cell to cell and throughout the brain. This process is thought to lead to the templated misfolding of the native forms of tau, and thereby, to the formation of newer toxic aggregates, thereby propagating the disease. Therefore, modulation of the processes that lead to tau aggregation and spreading is of utmost importance in the fight against tauopathies. In recent years, several molecules have been developed for the modulation of tau aggregation and spreading. In this review, we discuss the processes of tau aggregation and spreading and highlight selected chemicals developed for the modulation of these processes, their usefulness, and putative mechanisms of action. Ultimately, a stronger understanding of the molecular mechanisms involved, and the properties of the substances developed to modulate them, will lead to the development of safer and better strategies for the treatment of tauopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/brainsci10110858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696562PMC
November 2020

Increased expression of myelin-associated genes in frontal cortex of overexpressing rats and Parkinson's disease patients.

Aging (Albany NY) 2020 Oct 5;12(19):18889-18906. Epub 2020 Oct 5.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen 72076, Germany.

Parkinson's disease (PD) is an age-dependent neurodegenerative disorder. Besides characteristic motor symptoms, patients suffer from cognitive impairments linked to pathology in cortical areas. Due to obvious challenges in tracing the underlying molecular perturbations in human brain over time, we took advantage of a well-characterized PD rat model. Using RNA sequencing, we profiled the frontocortical transcriptome of post-mortem patient samples and aligned expression changes with perturbation patterns obtained in the model at 5 and 12 months of age reflecting a presymptomatic and symptomatic time point. Integrating cell type-specific reference data, we identified a shared expression signature between both species that pointed to oligodendrocyte-specific, myelin-associated genes. Drawing on longitudinal information from the model, their nearly identical upregulation in both species could be traced to two distinctive perturbance modes. While one mode exhibited age-independent alterations that affected genes including proteolipid protein 1 (), the other mode, impacting on genes like myelin-associated glycoprotein (), was characterized by interferences of disease gene and adequate expression adaptations along aging. Our results highlight that even for a group of functionally linked genes distinct interference mechanisms may underlie disease progression that cannot be distinguished by examining the terminal point alone but instead require longitudinal interrogation of the system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.103935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732335PMC
October 2020

Bioprospection of Natural Sources of Polyphenols with Therapeutic Potential for Redox-Related Diseases.

Antioxidants (Basel) 2020 Aug 26;9(9). Epub 2020 Aug 26.

CEDOC, Chronic Diseases Research Centre, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056 Lisboa, Portugal.

Plants are a reservoir of high-value molecules with underexplored biomedical applications. With the aim of identifying novel health-promoting attributes in underexplored natural sources, we scrutinized the diversity of (poly)phenols present within the berries of selected germplasm from cultivated, wild, and underutilized species. Our strategy combined the application of metabolomics, statistical analysis, and evaluation of (poly)phenols' bioactivity using a yeast-based discovery platform. We identified species as sources of (poly)phenols interfering with pathological processes associated with redox-related diseases, particularly, amyotrophic lateral sclerosis, cancer, and inflammation. In silico prediction of putative bioactives suggested cyanidin-hexoside as an anti-inflammatory molecule which was validated in yeast and mammalian cells. Moreover, cellular assays revealed that the cyanidin moiety was responsible for the anti-inflammatory properties of cyanidin-hexoside. Our findings unveiled novel (poly)phenolic bioactivities and illustrated the power of our integrative approach for the identification of dietary (poly)phenols with potential biomedical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antiox9090789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576474PMC
August 2020

The Role of Alpha-Synuclein and Other Parkinson's Genes in Neurodevelopmental and Neurodegenerative Disorders.

Int J Mol Sci 2020 Aug 10;21(16). Epub 2020 Aug 10.

Department Pathology, Stanford University School of Medicine, Stanford, CA 94304, USA.

Neurodevelopmental and late-onset neurodegenerative disorders present as separate entities that are clinically and neuropathologically quite distinct. However, recent evidence has highlighted surprising commonalities and converging features at the clinical, genomic, and molecular level between these two disease spectra. This is particularly striking in the context of autism spectrum disorder (ASD) and Parkinson's disease (PD). Genetic causes and risk factors play a central role in disease pathophysiology and enable the identification of overlapping mechanisms and pathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD. Several genes and genomic regions were selected for our review, including (alpha-synuclein), (parkin RBR E3 ubiquitin protein ligase), chromosome 22q11 deletion/DiGeorge region, and (fragile X mental retardation 1) repeat expansion, which influence the development of both ASD and PD, with converging features related to synaptic function and neurogenesis. Both PD and ASD display alterations and impairments at the synaptic level, representing early and key disease phenotypes, which support the hypothesis of converging mechanisms between the two types of diseases. Therefore, understanding the underlying molecular mechanisms might inform on common targets and therapeutic approaches. We propose to re-conceptualize how we understand these disorders and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21165724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460874PMC
August 2020

Hsp27 reduces glycation-induced toxicity and aggregation of alpha-synuclein.

FASEB J 2020 05 7;34(5):6718-6728. Epub 2020 Apr 7.

CEDOC, Chronic Diseases Research Center, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.

α-synuclein (aSyn) is a major player in Parkinson's disease and a group of other disorders collectively known as synucleinopathies, but the precise molecular mechanisms involved are still unclear. aSyn, as virtually all proteins, undergoes a series of posttranslational modifications during its lifetime, which can affect its biology and pathobiology. We recently showed that glycation of aSyn by methylglyoxal (MGO) potentiates its oligomerization and toxicity, induces dopaminergic neuronal cell loss in mice, and affects motor performance in flies. Small heat-shock proteins (sHsps) are molecular chaperones that facilitate the folding of proteins or target misfolded proteins for clearance. Importantly, sHsps were shown to prevent aSyn aggregation and cytotoxicity. Upon treating cells with increasing amounts of methylglyoxal, we found that the levels of Hsp27 decreased in a dose-dependent manner. Therefore, we hypothesized that restoring the levels of Hsp27 in glycating environments could alleviate the pathogenicity of aSyn. Consistently, we found that Hsp27 reduced MGO-induced aSyn aggregation in cells, leading to the formation of nontoxic aSyn species. Remarkably, increasing the levels of Hsp27 suppressed the deleterious effects induced by MGO. Our findings suggest that in glycating environments, the levels of Hsp27 are important for modulating the glycation-associated cellular pathologies in synucleinopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201902936RDOI Listing
May 2020

Mechanisms of alpha-synuclein toxicity: An update and outlook.

Prog Brain Res 2020 23;252:91-129. Epub 2019 Nov 23.

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany; Max Planck Institute for Experimental Medicine, Göttingen, Germany; Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address:

Alpha-synuclein (aSyn) was identified as the main component of inclusions that define synucleinopathies more than 20 years ago. Since then, aSyn has been extensively studied in an attempt to unravel its roles in both physiology and pathology. Today, studying the mechanisms of aSyn toxicity remains in the limelight, leading to the identification of novel pathways involved in pathogenesis. In this chapter, we address the molecular mechanisms involved in synucleinopathies, from aSyn misfolding and aggregation to the various cellular effects and pathologies associated. In particular, we review our current understanding of the mechanisms involved in the spreading of aSyn between different cells, from the periphery to the brain, and back. Finally, we also review recent studies on the contribution of inflammation and the gut microbiota to pathology in synucleinopathies. Despite significant advances in our understanding of the molecular mechanisms involved, we still lack an integrated understanding of the pathways leading to neurodegeneration in PD and other synucleinopathies, compromising our ability to develop novel therapeutic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/bs.pbr.2019.10.005DOI Listing
January 2021

The courage to change science.

EMBO Rep 2020 03 20;21(3):e50124. Epub 2020 Feb 20.

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Goettingen, Germany.

Bureaucracy, performance assessment and other pressures increasingly encroach on scientists' ability to do science. The research community as a whole needs to address these perils.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/embr.202050124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054679PMC
March 2020

A new MAP-Rasagiline conjugate reduces α-synuclein inclusion formation in a cell model.

Pharmacol Rep 2020 Apr 15;72(2):456-464. Epub 2020 Jan 15.

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany.

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease of the elderly. Current therapies are only symptomatic, and have no disease-modifying effect. Therefore, disease progresses continuously over time, presenting with both motor and non-motor features. The precise molecular basis for PD is still elusive, but the aggregation of the protein alpha-synuclein (α-syn) is a key pathological hallmark of the disease and is, therefore, a major focus of current research. Considering the intrinsic properties of cell-penetrating peptides (CPPs) for mediating drug delivery of neurotherapeutics across the blood brain barrier (BBB), these might open novel opportunities for the development of new solutions for the treatment of brain-related aspects of PD and other neurodegenerative disorders.

Methods: Here, we synthesized solid-phase CPPs using an amphipathic model peptide (MAP) conjugated with the drug Rasagiline (RAS), which we named RAS-MAP, and evaluated its effect on α-syn inclusion formation in a human cell-based model of synucleinopathy.

Results: We found that treatment with RAS-MAP at low concentrations (1-3 µM) reduced α-syn aggregation in cells.

Conclusions: For the first time, we report that conjugation of a current drug used in the therapy of PD with CPP reduces α-syn aggregation, which might prove beneficial in PD and other synucleinopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s43440-019-00032-xDOI Listing
April 2020

Synucleinopathies: Where we are and where we need to go.

J Neurochem 2020 05 19;153(4):433-454. Epub 2020 Feb 19.

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.

Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a-synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019: Where we are and where we need to go", brought together >300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jnc.14965DOI Listing
May 2020

Characterization of the activity, aggregation, and toxicity of heterodimers of WT and ALS-associated mutant Sod1.

Proc Natl Acad Sci U S A 2019 12 3;116(51):25991-26000. Epub 2019 Dec 3.

Institute of Chemistry, Federal University of Rio de Janeiro, 21941-909 Rio de Janeiro, RJ, Brazil;

Mutations in Cu/Zn superoxide dismutase (Sod1) have been reported in both familial and sporadic amyotrophic lateral sclerosis (ALS). In this study, we investigated the behavior of heteromeric combinations of wild-type (WT) and mutant Sod1 proteins A4V, L38V, G93A, and G93C in human cells. We showed that both WT and mutant Sod1 formed dimers and oligomers, but only mutant Sod1 accumulated in intracellular inclusions. Coexpression of WT and hSod1 mutants resulted in the formation of a larger number of intracellular inclusions per cell than that observed in cells coexpressing WT or mutant hSod1. The number of inclusions was greater in cells expressing A4V hSod1. To eliminate the contribution of endogenous Sod1, and better evaluate the effect of ALS-associated mutant Sod1 expression, we expressed human Sod1 WT and mutants in human cells knocked down for endogenous Sod1 (Sod1-KD), and in yeast cells. Using Sod1-KD cells we found that the WT-A4V heteromers formed higher molecular weight species compared with A4V and WT homomers. Using the yeast model, in conditions of chronological aging, we concluded that cells expressing Sod1 heterodimers showed decreased antioxidant activity, increased oxidative damage, reduced longevity, and oxidative stress-induced mutant Sod1 aggregation. In addition, we also found that ALS-associated Sod1 mutations reduced nuclear localization and, consequently, impaired the antioxidant response, suggesting this change in localization may contribute to disease in familial ALS. Overall, our study provides insight into the molecular underpinnings of ALS and may open avenues for the design of future therapeutic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1902483116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926019PMC
December 2019

Synuclein Meeting 2019: where we are and where we need to go.

J Neurochem 2019 09;150(5):462-466

Parkinson's Disease and Movement Disorders Center, Division of Neurology, Department of Medicine, The Ottawa Hospital Research Institute, Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada.

The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein Meeting is taking place in Ofir, a city in the outskirts of Porto, Portugal. The meeting is entitled 'Synuclein Meeting 2019: Where we are and where we need to go'. It has now been 22 years since the initial report of the genetic and pathological association between alpha-synuclein and Parkinson's disease (PD). The field has grown and matured, and major advances have been made. We are witnessing exciting times, with the first clinical trials being conducted that target synuclein, and bring the hope of novel therapies for patients with PD and their families. However, we still face many challenges and need to address fundamental questions for the field to progress to where we need to go: having biomarkers and effective therapies for PD and other synucleinopathies. In this context, we have designed the Synuclein Meeting 2019 with a different format. The program will include sessions in the format of a round-table discussion, to break away from the more rigid format of regular scientific meetings based on oral presentations. Our goal was to create opportunities for discussing the major questions in the field of synuclein and related human disorders, and challenge dogmatic ideas that require a critical revision in light of the most recent knowledge. In this issue, we assembled a series of comprehensive overviews of major topics, questions, and challenges in the field, that will be discussed in the meeting. We are confident that this special issue will be an instrumental reference for inspiring novel paths for future discoveries in the synuclein field and generate other discussions in the scientific community. This is the Preface for the Special Issue "Synuclein". Cover Image for this issue: doi: 10.1111/jnc.14520.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jnc.14825DOI Listing
September 2019

Epigenetics of the Synapse in Neurodegeneration.

Curr Neurol Neurosci Rep 2019 08 23;19(10):72. Epub 2019 Aug 23.

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Waldweg 33, 37073, Göttingen, Germany.

Purpose Of Review: In the quest for understanding the pathophysiological processes underlying degeneration of nervous systems, synapses are emerging as sites of great interest as synaptic dysfunction is thought to play a role in the initiation and progression of neuronal loss. In particular, the synapse is an interesting target for the effects of epigenetic mechanisms in neurodegeneration. Here, we review the recent advances on epigenetic mechanisms driving synaptic compromise in major neurodegenerative disorders.

Recent Findings: Major developments in sequencing technologies enabled the mapping of transcriptomic patterns in human postmortem brain tissues in various neurodegenerative diseases, and also in cell and animal models. These studies helped identify changes in classical neurodegeneration pathways and discover novel targets related to synaptic degeneration. Identifying epigenetic patterns indicative of synaptic defects prior to neuronal degeneration may provide the basis for future breakthroughs in the field of neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11910-019-0995-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706357PMC
August 2019

Glycation in Huntington's Disease: A Possible Modifier and Target for Intervention.

J Huntingtons Dis 2019 ;8(3):245-256

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.

Glycation is the non-enzymatic reaction between reactive dicarbonyls and amino groups, and gives rise to a variety of different reaction products known as advanced glycation end products (AGEs). Accumulation of AGEs on proteins is inevitable, and is associated with the aging process. Importantly, glycation is highly relevant in diabetic patients that experience periods of hyperglycemia. AGEs also play an important role in neurodegenerative diseases including Alzheimer's (AD) and Parkinson's disease (PD). Huntington's disease (HD) is a hereditary neurodegenerative disease caused by an expansion of a CAG repeat in the huntingtin gene. The resulting expanded polyglutamine stretch in the huntingtin (HTT) protein induces its misfolding and aggregation, leading to neuronal dysfunction and death. HD patients exhibit chorea and psychiatric disturbances, along with abnormalities in glucose and energy homeostasis. Interestingly, an increased prevalence of diabetes mellitus has been reported in HD and in other CAG triplet repeat disorders. However, the mechanisms underlying the connection between glycation and HD progression remain unclear. In this review, we explore the possible connection between glycation and proteostasis imbalances in HD, and posit that it may contribute to disease progression, possibly by accelerating protein aggregation and deposition. Finally, we review therapeutic interventions that might be able to alleviate the negative impact of glycation in HD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JHD-190366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839463PMC
July 2020

Spreading of α-Synuclein and Tau: A Systematic Comparison of the Mechanisms Involved.

Front Mol Neurosci 2019 25;12:107. Epub 2019 Apr 25.

Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Goettingen, Germany.

Alzheimer's disease (AD) and Parkinson's disease (PD) are age-associated neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn) and tau, respectively. The coexistence of aSyn and tau aggregates suggests a strong overlap between tauopathies and synucleinopathies. Interestingly, misfolded forms of aSyn and tau can propagate from cell to cell, and throughout the brain, thereby templating the misfolding of native forms of the proteins. The exact mechanisms involved in the propagation of the two proteins show similarities, and are reminiscent of the spreading characteristic of prion diseases. Recently, several models were developed to study the spreading of aSyn and tau. Here, we discuss the mechanisms involved, the similarities and differences between the spreading of the two proteins and that of the prion protein, and the different cell and animal models used for studying these processes. Ultimately, a deeper understanding of the molecular mechanisms involved may lead to the identification of novel targets for therapeutic intervention in a variety of devastating neurodegenerative diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnmol.2019.00107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494944PMC
April 2019

LRRK2, alpha-synuclein, and tau: partners in crime or unfortunate bystanders?

Biochem Soc Trans 2019 06 13;47(3):827-838. Epub 2019 May 13.

Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.

The identification of genetic forms of Parkinson's disease (PD) has tremendously expanded our understanding of the players and mechanisms involved. Mutations in the genes encoding for alpha-synuclein (aSyn), LRRK2, and tau have been associated with familial and sporadic forms of the disease. aSyn is the major component of Lewy bodies and Lewy neurites, which are pathognomonic protein inclusions in PD. Hyperphosphorylated tau protein accumulates in neurofibrillary tangles in the brains of Alzheimer's disease patients but is also seen in the brains of PD patients. LRRK2 is a complex multi-domain protein with kinase and GTPase enzymatic activity. Since aSyn and tau are phosphoproteins, we review the possible interplay between the three proteins. Understanding the interplay between LRRK2, aSyn and tau is extremely important, as this may enable the identification of novel targets and pathways for therapeutic intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/BST20180466DOI Listing
June 2019

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies.

J Neurochem 2019 09 15;150(5):535-565. Epub 2019 May 15.

Institute of Neuroscience, The Medical School, Newcastle University, Newcastle Upon Tyne, UK.

Alpha-synuclein (α-Syn) is a central player in Parkinson's disease (PD) and in a spectrum of neurodegenerative diseases collectively known as synucleinopathies. The protein was first associated with PD just over 20 years ago, when it was found to (i) be a major component of Lewy bodies and (ii) to be also associated with familial forms of PD. The characterization of α-Syn pathology has been achieved through postmortem studies of human brains. However, the identification of toxic mechanisms associated with α-Syn was only achieved through the use of experimental models. In vitro models are highly accessible, enable relatively rapid studies, and have been extensively employed to address α-Syn-associated neurodegeneration. Given the diversity of models used and the outcomes of the studies, a cumulative and comprehensive perspective emerges as indispensable to pave the way for further investigations. Here, we subdivided in vitro models of α-Syn pathology into three major types: (i) models simulating α-Syn fibrillization and the formation of different aggregated structures in vitro, (ii) models based on the intracellular expression of α-Syn, reporting on pathogenic conditions and cellular dysfunctions induced, and (iii) models using extracellular treatment with α-Syn aggregated species, reporting on sites of interaction and their downstream consequences. In summary, we review the underlying molecular mechanisms discovered and categorize protective strategies, in order to pave the way for future studies and the identification of effective therapeutic strategies. This article is part of the Special Issue "Synuclein".
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jnc.14707DOI Listing
September 2019

Dementia with Lewy bodies: an update and outlook.

Mol Neurodegener 2019 01 21;14(1). Epub 2019 Jan 21.

Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK.

Dementia with Lewy bodies (DLB) is an age-associated neurodegenerative disorder producing progressive cognitive decline that interferes with normal life and daily activities. Neuropathologically, DLB is characterised by the accumulation of aggregated α-synuclein protein in Lewy bodies and Lewy neurites, similar to Parkinson's disease (PD). Extrapyramidal motor features characteristic of PD, are common in DLB patients, but are not essential for the clinical diagnosis of DLB. Since many PD patients develop dementia as disease progresses, there has been controversy about the separation of DLB from PD dementia (PDD) and consensus reports have put forward guidelines to assist clinicians in the identification and management of both syndromes. Here, we present basic concepts and definitions, based on our current understanding, that should guide the community to address open questions that will, hopefully, lead us towards improved diagnosis and novel therapeutic strategies for DLB and other synucleinopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13024-019-0306-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341685PMC
January 2019

Sensing α-Synuclein From the Outside via the Prion Protein: Implications for Neurodegeneration.

Mov Disord 2018 11 13;33(11):1675-1684. Epub 2018 Nov 13.

Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.

Parkinson's disease and other synucleinopathies are characterized by the accumulation of aggregated α-synuclein in intracellular proteinaceous inclusions. The progressive nature of synucleinopathies seems to be related to the cell-to-cell spreading of α-synuclein pathology, and several possible mechanisms have been put forward to explain this phenomenon. In our recent study, we found that α-synuclein oligomers interact with cellular prion protein in glutamatergic synapses. This interaction triggered a signaling cascade involving phosphorylation of Fyn kinase and activation of the N-methyl-d-aspartate receptor, thereby leading to synaptic dysfunction. Here, we present relevant plasma membrane proteins that have been described to interact with α-synuclein and discuss the possible pathological implications. We focus primarily on the prion protein and propose a pathological mechanism in which the interaction between α-synuclein and prion protein leads to the formation of cofilin/actin rods, culminating in long-term potentiation impairment and cognitive dysfunction. We posit that deciphering the mechanisms involved in sensing specific forms of extracellular α-synuclein and transducing this information may prove invaluable in our quest to devise novel diagnostic and therapeutic approaches in PD and other synucleinopathies. © 2018 International Parkinson and Movement Disorder Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.27478DOI Listing
November 2018

Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons.

Proc Natl Acad Sci U S A 2018 10 24;115(41):10481-10486. Epub 2018 Sep 24.

Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain;

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of intracellular protein inclusions, known as Lewy bodies and Lewy neurites, which are mainly composed of α-synuclein. Here, we exploited a high-throughput screening methodology to identify a small molecule (SynuClean-D) able to inhibit α-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wild-type α-synuclein and the familiar A30P and H50Q variants in a substoichiometric molar ratio. This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of α-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature α-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD models, expressing α-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by α-synuclein. SynuClean-D-treated worms show decreased α-synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from α-synuclein-induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1804198115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187188PMC
October 2018

Alpha-Synuclein Glycation and the Action of Anti-Diabetic Agents in Parkinson's Disease.

J Parkinsons Dis 2018 ;8(1):33-43

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany.

Parkinson's disease (PD) is a neurodegenerative disorder with complex etiology and variable pathology. While a subset of cases is associated with single-gene mutations, the majority originates from a combination of factors we do not fully understand. Thus, understanding the underlying causes of PD is indispensable for the development of novel therapeutics. Glycation, the non-enzymatic reaction between reactive dicarbonyls and amino groups, gives rise to a variety of different reaction products known as advanced glycation end products (AGEs). AGEs accumulate over a proteins life-time, and increased levels of glycation reaction products play a role in diabetic complications. It is now also becoming evident that PD patients also display perturbed sugar metabolism and protein glycation, including that of alpha-synuclein, a key player in PD. Here, we hypothesize that anti-diabetic drugs targeting the levels of glycation precursors, or promoting the clearance of glycated proteins may also prove beneficial for PD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JPD-171285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842785PMC
October 2019

Posttranslational modifications of blood-derived alpha-synuclein as biochemical markers for Parkinson's disease.

Sci Rep 2017 10 20;7(1):13713. Epub 2017 Oct 20.

CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal.

Parkinson's disease (PD) is a progressive neurodegenerative disorder known for the typical motor features associated. Pathologically, it is characterized by the intracellular accumulation of alpha-synuclein (aSyn) in Lewy bodies and Lewy neurites. Currently, there are no established biochemical markers for diagnosing or for following disease progression, a major limitation for the clinical practice. Posttranslational modifications (PTMs) in aSyn have been identified and implicated on its pathobiology. Since aSyn is abundant in blood erythrocytes, we aimed to evaluate whether PTMs of aSyn in the blood might hold value as a biomarker for PD. We examined 58 patients with PD and 30 healthy age-matched individuals. We found that the levels of Y125 phosphorylated, Y39 nitrated, and glycated aSyn were increased in PD, while those of SUMO were reduced. A combinatory analysis of the levels of these PTMs resulted in an increased sensitivity, with an area under curve (AUC) of 0.843 for PD versus healthy controls, and correlated with disease severity and duration. We conclude that the levels of these selected PTMs hold strong potential as biochemical markers for PD. Ultimately, our findings might facilitate the monitoring of disease progression in clinical trials, opening the possibility for developing more effective therapies against PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-14175-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651848PMC
October 2017

Serum lipid alterations in GBA-associated Parkinson's disease.

Parkinsonism Relat Disord 2017 Nov 1;44:58-65. Epub 2017 Sep 1.

Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Laboratorio de Genetica, Faculty of Medicine, University of Lisbon, Portugal; Portuguese Reference Center of Lysosomal Storage Diseases, Hospital Senhora de Oliveira Guimaraes / University of Minho, Braga, Portugal. Electronic address:

Introduction: Mutations in the GBA gene, encoding for the lysosomal enzyme glucocerebrosidase, are associated with Gaucher disease. Alterations in plasma sphingolipids have been reported in Gaucher, and similarly in brain extracts in Lewy body disease. As GBA mutations are prevalent risk factors for Parkinson's disease and overlap of molecular pathways are presumable, here we assessed the lipid profiles in Parkinson's patients with and without GBA mutations.

Methods: We sequenced all GBA exons in 415 Parkinson's patients, previously genotyped for LRRK2. 64 patients (29 GBA positive vs. 35 non-GBA-carriers including 18 LRRK2 positive and 17 non-mutated) were analyzed for chitotriosidase activity and for the concentration of 40 lipid classes using HPLC-MS.

Results: 29/415 patients (6.9%) carried 8 different GBA mutations associated with Gaucher or Parkinson's, including one novel mutation. Chitotriosidase activity was similar across the genetic groups, while the levels of key lipids were altered in GBA mutation carriers: Monohexosylceramide, Ceramide and Sphingomyelin were elevated; while Phosphatidic acid (PA), Phosphatidylethanolamine (PE), Plasmalogen phosphatidylethanolamine (PEp) and Acyl Phosphatidylglycerol (AcylPG) were decreased.

Conclusion: The results suggest an important role for these lipids in GBA mediated Parkinson's disease and assist in the identification of common pathways between Gaucher and Parkinson's. Ultimately, our findings may lead to the identification of novel biomarkers for individuals at increased risk of developing Parkinson's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2017.08.026DOI Listing
November 2017

Cellular models as tools for the study of the role of alpha-synuclein in Parkinson's disease.

Exp Neurol 2017 12 16;298(Pt B):162-171. Epub 2017 May 16.

Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, 37073 Göttingen, Germany; Max Planck Institute for Experimental Medicine, Goettingen, Germany. Electronic address:

Neurodegenerative diseases are highly debilitating conditions characterised primarily by progressive neuronal loss and impairment of the nervous system. Parkinson's disease (PD) is one of the most common of these disorders, affecting 1-2% of the population above the age of 65. Although the underlying mechanisms of PD have been extensively studied, we still lack a full understanding of the molecular underpinnings of the disease. Thus, the in vitro and in vivo models currently used are able to only partially recapitulate the typical phenotypes of the disease. Here, we review various cell culture models currently used to study the molecular basis of PD, with a focus on alpha-synuclein-associated molecular pathologies. We also discuss how different cell models may constitute powerful tools for high-throughput screening of molecules capable of modulating alpha-synuclein toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.expneurol.2017.05.007DOI Listing
December 2017

Epigenetics in Parkinson's Disease.

Adv Exp Med Biol 2017 ;978:363-390

Department of NeuroDegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany.

Parkinson's disease (PD) is a highly complex neurodegenerative disorder with a multifactorial origin. Although several cellular mechanisms and genes have been implicated in the onset and progression of the disease, the precise molecular underpinnings of the disease remain unclear. In this context, epigenetic modulation of gene expression by environmental factors is emerging as an important mechanism in PD and in other neurodegenerative disorders. Thus, epigenetic mechanisms, such as DNA methylation, histone modifications and altered microRNA expression, have been under intense investigation due to their possible involvement in PD. Epigenetic modulation is responsible for inducing differential gene expression, a phenomenon which is essential throughout life in order to regulate multiple cellular responses such as development, cellular fate commitment and adaptation to the environment. Disturbances of a balanced gene expression can, therefore, have detrimental effects. Environmental factors can challenge the establishment and maintenance of epigenetic modifications and could thereby fill the gap in our further understanding of origin and/or progression of neurodegenerative diseases. In this chapter, we focus on the role of epigenetics in PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-3-319-53889-1_19DOI Listing
September 2017