Publications by authors named "Andreas Hermann"

217 Publications

A SARS-CoV-2 neutralizing antibody selected from COVID-19 patients binds to the ACE2-RBD interface and is tolerant to most known RBD mutations.

Cell Rep 2021 Jul 7:109433. Epub 2021 Jul 7.

Städtisches Klinikum Braunschweig gGmbH, Holwedestraße 16, 38118 Braunschweig, Germany.

The novel betacoronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) causes a form of severe pneumonia disease called coronavirus disease 2019 (COVID-19). To develop human neutralizing anti-SARS-CoV-2 antibodies, antibody gene libraries from convalescent COVID-19 patients were constructed and recombinant antibody fragments (scFv) against the receptor-binding domain (RBD) of the spike protein were selected by phage display. The antibody STE90-C11 shows a subnanometer IC in a plaque-based live SARS-CoV-2 neutralization assay. The in vivo efficacy of the antibody is demonstrated in the Syrian hamster and in the human angiotensin-converting enzyme 2 (hACE2) mice model. The crystal structure of STE90-C11 Fab in complex with SARS-CoV-2-RBD is solved at 2.0 Å resolution showing that the antibody binds at the same region as ACE2 to RBD. The binding and inhibition of STE90-C11 is not blocked by many known emerging RBD mutations. STE90-C11-derived human IgG1 with FcγR-silenced Fc (COR-101) is undergoing Phase Ib/II clinical trials for the treatment of moderate to severe COVID-19.
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http://dx.doi.org/10.1016/j.celrep.2021.109433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260561PMC
July 2021

Informal Caregiving in Amyotrophic Lateral Sclerosis (ALS): A High Caregiver Burden and Drastic Consequences on Caregivers' Lives.

Brain Sci 2021 Jun 4;11(6). Epub 2021 Jun 4.

Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients' informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs ( = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King's Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (r = -0.555, < 0.001, 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], < 0.001), patients' wheelchair dependency (+9.30, 95% CI [5.94; 12.66], < 0.001) and was interrelated with the CGs' depression (r = 0.627, < 0.001, 234), anxiety (r = 0.550, < 0.001, 234), and poorer physical condition (r = -0.362, < 0.001, 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (r = -0.280, < 0.001, 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.
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http://dx.doi.org/10.3390/brainsci11060748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228206PMC
June 2021

Cardiac manifestation is evident in chorea-acanthocytosis but different from McLeod syndrome.

Parkinsonism Relat Disord 2021 Jul 24;88:90-95. Epub 2021 May 24.

Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology, University Medical Center, University of Rostock, Rostock, Germany. Electronic address:

Introduction: We aimed to study the various cardiac manifestations of the two core neuroacanthocytosis (NA) syndromes, namely chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS). So far, cardiac involvement has been described as specific feature only for MLS.

Methods: We studied six patients with ChAc (mean age 44.5 years, five men, one woman) and six patients with MLS (mean age 57.1 years, all men). Cardiac evaluation included echocardiography and/or cardiac magnetic resonance imaging (cardiac MRI), 24-h ECG-recording and examination of cardiac biomarkers.

Results: Cardiac involvement of ChAc was found in four of six patients. Two patients showed mildly reduced left ventricular ejection fraction (LVEF), two other patients mild to moderate left ventricular (LV) dilatation. Neither an increase in ventricular ectopic beats nor ventricular tachycardia were evident in ChAc. Four of five MLS patients showed left ventricle dilatation and reduced left ventricular ejection fraction (LVEF). Two of these, in addition, had critical ventricular tachycardia. High sensitive troponin T was elevated in all patients, for whom data were available (n = 10). In contrast, elevation of high sensitive troponin I was found in one of six ChAc and one of two MLS patients.

Conclusion: For the first time, we reveal cardiac involvement in a cohort of six ChAc patients, while the risk to develop heart failure seems lower than in MLS. Our study confirms the malignant nature of MLS in terms of ventricular arrhythmias and progression to advanced heart failure. Herein, we define disease-specific recommendations for cardiac assessment in both conditions.
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http://dx.doi.org/10.1016/j.parkreldis.2021.05.015DOI Listing
July 2021

Reduced Expression of GABA Receptor Alpha2 Subunit Is Associated With Disinhibition of DYT-THAP1 Dystonia Patient-Derived Striatal Medium Spiny Neurons.

Front Cell Dev Biol 2021 21;9:650586. Epub 2021 May 21.

Department of Neurology, Hannover Medical School, Hanover, Germany.

DYT-THAP1 dystonia (formerly DYT6) is an adolescent-onset dystonia characterized by involuntary muscle contractions usually involving the upper body. It is caused by mutations in the gene encoding for the transcription factor Thanatos-associated protein (THAP) domain containing apoptosis-associated protein 1 and inherited in an autosomal-dominant manner with reduced penetrance. Alterations in the development of striatal neuronal projections and synaptic function are known from transgenic mice models. To investigate pathogenetic mechanisms, human induced pluripotent stem cell (iPSC)-derived medium spiny neurons (MSNs) from two patients and one family member with reduced penetrance carrying a mutation in the gene (c.474delA and c.38G > A) were functionally characterized in comparison to healthy controls. Calcium imaging and quantitative PCR analysis revealed significantly lower Ca amplitudes upon GABA applications and a marked downregulation of the gene encoding the GABA receptor alpha2 subunit in THAP1 MSNs indicating a decreased GABAergic transmission. Whole-cell patch-clamp recordings showed a significantly lower frequency of miniature postsynaptic currents (mPSCs), whereas the frequency of spontaneous action potentials (APs) was elevated in THAP1 MSNs suggesting that decreased synaptic activity might have resulted in enhanced generation of APs. Our molecular and functional data indicate that a reduced expression of GABA receptor alpha2 subunit could eventually lead to limited GABAergic synaptic transmission, neuronal disinhibition, and hyperexcitability of THAP1 MSNs. These data give pathophysiological insight and may contribute to the development of novel treatment strategies for DYT-THAP1 dystonia.
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http://dx.doi.org/10.3389/fcell.2021.650586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176025PMC
May 2021

Ranking Biomarkers of Aging by Citation Profiling and Effort Scoring.

Front Genet 2021 21;12:686320. Epub 2021 May 21.

Institute of Clinical Chemistry and Laboratory Medicine, Rostock University Medical Center, Rostock, Germany.

Aging affects most living organisms and includes the processes that reduce health and survival. The chronological and the biological age of individuals can differ remarkably, and there is a lack of reliable biomarkers to monitor the consequences of aging. In this review we give an overview of commonly mentioned and frequently used potential aging-related biomarkers. We were interested in biomarkers of aging in general and in biomarkers related to cellular senescence in particular. To answer the question whether a biological feature is relevant as a potential biomarker of aging or senescence in the scientific community we used the PICO strategy known from evidence-based medicine. We introduced two scoring systems, aimed at reflecting biomarker relevance and measurement effort, which can be used to support study designs in both clinical and research settings.
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http://dx.doi.org/10.3389/fgene.2021.686320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176216PMC
May 2021

Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease.

J Pers Med 2021 May 10;11(5). Epub 2021 May 10.

Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.

Chorea-acanthocytosis (ChAc) is a neurodegenerative disease caused by mutations in the gene. It is characterized by several neurological symptoms and the appearance of acanthocytes. Elevated tyrosine kinase Lyn activity has been recently identified as one of the key pathophysiological mechanisms in this disease, and therefore represents a promising drug target. We evaluated an individual off-label treatment with the tyrosine kinase inhibitor dasatinib (100 mg/d, 25.8-50.4 weeks) of three ChAc patients. Alongside thorough safety monitoring, we assessed motor and non-motor scales (e.g., MDS-UPDRS, UHDRS, quality of life) as well as routine and experimental laboratory parameters (e.g., serum neurofilament, Lyn kinase activity, actin cytoskeleton in red blood cells). Dasatinib appeared to be reasonably safe. The clinical parameters remained stable without significant improvement or deterioration. Regain of deep tendon reflexes was observed in one patient. Creatine kinase, serum neurofilament levels, and acanthocyte count did not reveal consistent effects. However, a reduction of initially elevated Lyn kinase activity and accumulated autophagy markers, as well as a partial restoration of the actin cytoskeleton, was found in red blood cells. We report on the first treatment approach with disease-modifying intention in ChAc. The experimental parameters indicate target engagement in red blood cells, while clinical effects on the central nervous system could not be proven within a rather short treatment time. Limited knowledge on the natural history of ChAc and the lack of appropriate biomarkers remain major barriers for "clinical trial readiness". We suggest a panel of outcome parameters for future clinical trials in ChAc.
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http://dx.doi.org/10.3390/jpm11050392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150322PMC
May 2021

The Erythrocyte Sedimentation Rate and Its Relation to Cell Shape and Rigidity of Red Blood Cells from Chorea-Acanthocytosis Patients in an Off-Label Treatment with Dasatinib.

Biomolecules 2021 May 12;11(5). Epub 2021 May 12.

Theoretical Medicine and Biosciences, Saarland University, 66424 Homburg, Germany.

Background: Chorea-acanthocytosis (ChAc) is a rare hereditary neurodegenerative disease with deformed red blood cells (RBCs), so-called acanthocytes, as a typical marker of the disease. Erythrocyte sedimentation rate (ESR) was recently proposed as a diagnostic biomarker. To date, there is no treatment option for affected patients, but promising therapy candidates, such as dasatinib, a Lyn-kinase inhibitor, have been identified.

Methods: RBCs of two ChAc patients during and after dasatinib treatment were characterized by the ESR, clinical hematology parameters and the 3D shape classification in stasis based on an artificial neural network. Furthermore, mathematical modeling was performed to understand the contribution of cell morphology and cell rigidity to the ESR. Microfluidic measurements were used to compare the RBC rigidity between ChAc patients and healthy controls.

Results: The mechano-morphological characterization of RBCs from two ChAc patients in an off-label treatment with dasatinib revealed differences in the ESR and the acanthocyte count during and after the treatment period, which could not directly be related to each other. Clinical hematology parameters were in the normal range. Mathematical modeling indicated that RBC rigidity is more important for delayed ESR than cell shape. Microfluidic experiments confirmed a higher rigidity in the normocytes of ChAc patients compared to healthy controls.

Conclusions: The results increase our understanding of the role of acanthocytes and their associated properties in the ESR, but the data are too sparse to answer the question of whether the ESR is a suitable biomarker for treatment success, whereas a correlation between hematological and neuronal phenotype is still subject to verification.
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http://dx.doi.org/10.3390/biom11050727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151862PMC
May 2021

DDX17 is involved in DNA damage repair and modifies FUS toxicity in an RGG-domain dependent manner.

Acta Neuropathol 2021 Jun 1. Epub 2021 Jun 1.

Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Mutations in the RNA binding protein, Fused in Sarcoma (FUS), lead to amyotrophic lateral sclerosis (ALS), the most frequent form of motor neuron disease. Cytoplasmic aggregation and defective DNA repair machinery are etiologically linked to mutant FUS-associated ALS. Although FUS is involved in numerous aspects of RNA processing, little is understood about the pathophysiological mechanisms of mutant FUS. Here, we employed RNA-sequencing technology in Drosophila brains expressing FUS to identify significantly altered genes and pathways involved in FUS-mediated neurodegeneration. We observed the expression levels of DEAD-Box Helicase 17 (DDX17) to be significantly downregulated in response to mutant FUS in Drosophila and human cell lines. Mutant FUS recruits nuclear DDX17 into cytoplasmic stress granules and physically interacts with DDX17 through the RGG1 domain of FUS. Ectopic expression of DDX17 reduces cytoplasmic mislocalization and sequestration of mutant FUS into cytoplasmic stress granules. We identified DDX17 as a novel regulator of the DNA damage response pathway whose upregulation repairs defective DNA damage repair machinery caused by mutant neuronal FUS ALS. In addition, we show DDX17 is a novel modifier of FUS-mediated neurodegeneration in vivo. Our findings indicate DDX17 is downregulated in response to mutant FUS, and restoration of DDX17 levels suppresses FUS-mediated neuropathogenesis and toxicity in vivo.
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http://dx.doi.org/10.1007/s00401-021-02333-zDOI Listing
June 2021

Pathomechanisms of ALS8: altered autophagy and defective RNA binding protein (RBP) homeostasis due to the VAPB P56S mutation.

Cell Death Dis 2021 May 10;12(5):466. Epub 2021 May 10.

Institute of Neuropathology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074, Aachen, Germany.

Mutations in RNA binding proteins (RBPs) and in genes regulating autophagy are frequent causes of familial amyotrophic lateral sclerosis (fALS). The P56S mutation in vesicle-associated membrane protein-associated protein B (VAPB) leads to fALS (ALS8) and spinal muscular atrophy (SMA). While VAPB is primarily involved in the unfolded protein response (UPR), vesicular trafficking and in initial steps of the autophagy pathway, the effect of mutant P56S-VAPB on autophagy regulation in connection with RBP homeostasis has not been explored yet. Examining the muscle biopsy of our index ALS8 patient of European origin revealed globular accumulations of VAPB aggregates co-localised with autophagy markers LC3 and p62 in partially atrophic and atrophic muscle fibres. In line with this skin fibroblasts obtained from the same patient showed accumulation of P56S-VAPB aggregates together with LC3 and p62. Detailed investigations of autophagic flux in cell culture models revealed that P56S-VAPB alters both initial and late steps of the autophagy pathway. Accordingly, electron microscopy complemented with live cell imaging highlighted the impaired fusion of accumulated autophagosomes with lysosomes in cells expressing P56S-VAPB. Consistent with these observations, neuropathological studies of brain and spinal cord of P56S-VAPB transgenic mice revealed signs of neurodegeneration associated with altered protein quality control and defective autophagy. Autophagy and RBP homeostasis are interdependent, as demonstrated by the cytoplasmic mis-localisation of several RBPs including pTDP-43, FUS, Matrin 3 which often sequestered with P56S-VAPB aggregates both in cell culture and in the muscle biopsy of the ALS8 patient. Further confirming the notion that aggregation of the RBPs proceeds through the stress granule (SG) pathway, we found persistent G3BP- and TIAR1-positive SGs in P56S-VAPB expressing cells as well as in the ALS8 patient muscle biopsy. We conclude that P56S-VAPB-ALS8 involves a cohesive pathomechanism of aberrant RBP homeostasis together with dysfunctional autophagy.
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http://dx.doi.org/10.1038/s41419-021-03710-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110809PMC
May 2021

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis.

Acta Neuropathol Commun 2021 05 3;9(1):81. Epub 2021 May 3.

Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Chorea-Acanthocytosis (ChAc) is a devastating, little understood, and currently untreatable neurodegenerative disease caused by VPS13A mutations. Based on our recent demonstration that accumulation of activated Lyn tyrosine kinase is a key pathophysiological event in human ChAc cells, we took advantage of Vps13a mice, which phenocopied human ChAc. Using proteomic approach, we found accumulation of active Lyn, γ-synuclein and phospho-tau proteins in Vps13a basal ganglia secondary to impaired autophagy leading to neuroinflammation. Mice double knockout Vps13a Lyn showed normalization of red cell morphology and improvement of autophagy in basal ganglia. We then in vivo tested pharmacologic inhibitors of Lyn: dasatinib and nilotinib. Dasatinib failed to cross the mouse brain blood barrier (BBB), but the more specific Lyn kinase inhibitor nilotinib, crosses the BBB. Nilotinib ameliorates both Vps13a hematological and neurological phenotypes, improving autophagy and preventing neuroinflammation. Our data support the proposal to repurpose nilotinib as new therapeutic option for ChAc patients.
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http://dx.doi.org/10.1186/s40478-021-01181-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091687PMC
May 2021

Rules of formation of H-C-N-O compounds at high pressure and the fates of planetary ices.

Proc Natl Acad Sci U S A 2021 May;118(19)

Centre for Science at Extreme Conditions, The University of Edinburgh, Edinburgh EH9 3FD, United Kingdom;

The solar system's outer planets, and many of their moons, are dominated by matter from the H-C-N-O chemical space, based on solar system abundances of hydrogen and the planetary ices [Formula: see text]O, [Formula: see text], and [Formula: see text] In the planetary interiors, these ices will experience extreme pressure conditions, around 5 Mbar at the Neptune mantle-core boundary, and it is expected that they undergo phase transitions, decompose, and form entirely new compounds. While temperature will dictate the formation of compounds, ground-state density functional theory allows us to probe the chemical effects resulting from pressure alone. These structural developments in turn determine the planets' interior structures, thermal evolution, and magnetic field generation, among others. Despite its importance, the H-C-N-O system has not been surveyed systematically to explore which compounds emerge at high-pressure conditions, and what governs their stability. Here, we report on and analyze an unbiased crystal structure search among H-C-N-O compounds between 1 and 5 Mbar. We demonstrate that simple chemical rules drive stability in this composition space, which explains why the simplest possible quaternary mixture HCNO-isoelectronic to diamond-emerges as a stable compound and discuss dominant decomposition products of planetary ice mixtures.
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http://dx.doi.org/10.1073/pnas.2026360118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126778PMC
May 2021

Pathophysiological In Vitro Profile of Neuronal Differentiated Cells Derived from Niemann-Pick Disease Type C2 Patient-Specific iPSCs Carrying the Mutations c.58G>T/c.140G>T.

Int J Mol Sci 2021 Apr 13;22(8). Epub 2021 Apr 13.

Translational Neurodegeneration Section "Albrecht Kossel", Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany.

Niemann-Pick type C2 (NP-C2) disease is a rare hereditary disease caused by mutations in the gene. NPC2 is a small, soluble protein consisting of 151 amino acids, primarily expressed in late endosomes and lysosomes (LE/LY). Together with NPC1, a transmembrane protein found in these organelles, NPC2 accomplishes the exclusion of cholesterol; thus, both proteins are essential to maintain cellular cholesterol homeostasis. Consequently, mutations in the or gene result in pathophysiological accumulation of cholesterol and sphingolipids in LE/LY. The vast majority of Niemann-Pick type C disease patients, 95%, suffer from a mutation of , and only 5% display a mutation of . The biochemical phenotype of NP-C1 and NP-C2 appears to be indistinguishable, and both diseases share several commonalities in the clinical manifestation. Studies of the pathological mechanisms underlying NP-C2 are mostly based on NP-C2 animal models and NP-C2 patient-derived fibroblasts. Recently, we established induced pluripotent stem cells (iPSCs), derived from a donor carrying the mutations c.58G>T/c.140G>T. Here, we present a profile of pathophysiological in vitro features, shared by NP-C1 and NP-C2, of neural differentiated cells obtained from the patient specific iPSCs. Profiling comprised a determination of the NPC2 protein level, detection of cholesterol accumulation by filipin staining, analysis of oxidative stress, and determination of autophagy. As expected, the NPC2-deficient cells displayed a significantly reduced amount of NPC2 protein, and, accordingly, we observed a significantly increased amount of cholesterol. Most notably, NPC2-deficient cells displayed only a slight increase of reactive oxygen species (ROS), suggesting that they do not suffer from oxidative stress and express catalase at a high level. As a site note, comparable NPC1-deficient cells suffer from a lack of catalase and display an increased level of ROS. In summary, this cell line provides a valuable tool to gain deeper understanding, not only of the pathogenic mechanism of NP-C2, but also of NP-C1.
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http://dx.doi.org/10.3390/ijms22084009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069078PMC
April 2021

Acanthocyte Sedimentation Rate as a Diagnostic Biomarker for Neuroacanthocytosis Syndromes: Experimental Evidence and Physical Justification.

Cells 2021 Apr 2;10(4). Epub 2021 Apr 2.

Experimental Physics, Saarland University, 66123 Saarbruecken, Germany.

(1) Background: Chorea-acanthocytosis and McLeod syndrome are the core diseases among the group of rare neurodegenerative disorders called neuroacanthocytosis syndromes (NASs). NAS patients have a variable number of irregularly spiky erythrocytes, so-called acanthocytes. Their detection is a crucial but error-prone parameter in the diagnosis of NASs, often leading to misdiagnoses. (2) Methods: We measured the standard Westergren erythrocyte sedimentation rate (ESR) of various blood samples from NAS patients and healthy controls. Furthermore, we manipulated the ESR by swapping the erythrocytes and plasma of different individuals, as well as replacing plasma with dextran. These measurements were complemented by clinical laboratory data and single-cell adhesion force measurements. Additionally, we followed theoretical modeling approaches. (3) Results: We show that the acanthocyte sedimentation rate (ASR) with a two-hour read-out is significantly prolonged in chorea-acanthocytosis and McLeod syndrome without overlap compared to the ESR of the controls. Mechanistically, through modern colloidal physics, we show that acanthocyte aggregation and plasma fibrinogen levels slow down the sedimentation. Moreover, the inverse of ASR correlates with the number of acanthocytes (R2=0.61, p=0.004). (4) Conclusions: The ASR/ESR is a clear, robust and easily obtainable diagnostic marker. Independently of NASs, we also regard this study as a hallmark of the physical view of erythrocyte sedimentation by describing anticoagulated blood in stasis as a percolating gel, allowing the application of colloidal physics theory.
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http://dx.doi.org/10.3390/cells10040788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067274PMC
April 2021

Fibular nailing for bi-malleolar and tri-malleolar ankle fractures yields good functional outcomes - a retrospective single-centre study.

Dan Med J 2021 Apr 20;68(5). Epub 2021 Apr 20.

Introduction: The surgical treatment of elderly patients with unstable ankle fractures is challenging. Open reduction and internal fixation with conventional plating technique often yields a poor outcome. However, fracture management with isolated fibular nailing represents an alternative method.

Methods: We performed a retrospective study of patients treated with isolated fibular nailing at the North Zealand Hospital, Denmark, between 1 January 2012 and 31 December 2016. A total of 58 patients were included. The primary outcome was post-operative function (dependency of a walking aid). Secondary outcomes were pain, radiographic union and complications (infection, fracture displacement and screw migration).

Results: At the last follow-up (mean follow-up of 10.3 months), 84.2% of the patients had returned to their baseline level of function. 18% had persistent pain. The last post-operative radiographic follow-up showed union in 93.7% of fractures of the lateral malleolus and 50% of the medial malleolus. The complication rate was 13.7%.

Conclusions: Isolated fibular nailing with immediate full weight bearing in plaster yields an acceptable functional outcome in elderly patients with unstable fractures of the malleoli.

Funding: none.

Trial Registration: not relevant.
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April 2021

Cognitive reserve and regional brain volume in amyotrophic lateral sclerosis.

Cortex 2021 06 17;139:240-248. Epub 2021 Mar 17.

German Centre for Neurodegenerative Diseases (DZNE), Rostock, Germany; Department of Neurology, University of Rostock, Rostock, Germany. Electronic address:

Objective: We investigated whether cognitive reserve measured by education and premorbid IQ allows amyotrophic lateral sclerosis patients to compensate for regional brain volume loss.

Methods: This was a cross-sectional study. We recruited sixty patients with amyotrophic lateral sclerosis from two specialist out-patient clinics. All participants underwent neuropsychological assessment; the outcomes were standardized z-scores reflecting verbal fluency, executive functions (shifting, planning, working memory), verbal memory and visuo-constructive ability. The predictor was regional brain volume. The moderating proxies of cognitive reserve were premorbid IQ (estimated by vocabulary) and educational years. We hypothesized that higher cognitive reserve would correlate with better performance on a cognitive test battery, and tested this hypothesis with Bayesian analysis of covariance.

Results: The analyses provided moderate to very strong evidence in favor of our hypothesis with regard to verbal fluency functions, working memory, verbal learning and recognition, and visuo-constructive ability (all BF > 3): higher cognitive reserve was associated with a mild increase in performance. For shifting and planning ability, the evidence was anecdotal.

Conclusions: These results indicate that cognitive reserve moderates the effect of brain morphology on cognition in ALS. Patients draw small but meaningful benefits from higher reserve, preserving fluency, memory and visuo-constructive functions. Executive functions presented a dissociation: verbally assessed functions benefitted from cognitive reserve, non-verbally assessed functions did not. This motivates future research into cognitive reserve in ALS and practical implications, such as strengthening reserve to delay decline.
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http://dx.doi.org/10.1016/j.cortex.2021.03.005DOI Listing
June 2021

A serum microRNA sequence reveals fragile X protein pathology in amyotrophic lateral sclerosis.

Brain 2021 May;144(4):1214-1229

Department of Neurology, Ulm University, Ulm, Germany.

Knowledge about converging disease mechanisms in the heterogeneous syndrome amyotrophic lateral sclerosis (ALS) is rare, but may lead to therapies effective in most ALS cases. Previously, we identified serum microRNAs downregulated in familial ALS, the majority of sporadic ALS patients, but also in presymptomatic mutation carriers. A 5-nucleotide sequence motif (GDCGG; D = G, A or U) was strongly enriched in these ALS-related microRNAs. We hypothesized that deregulation of protein(s) binding predominantly to this consensus motif was responsible for the ALS-linked microRNA fingerprint. Using microRNA pull-down assays combined with mass spectrometry followed by extensive biochemical validation, all members of the fragile X protein family, FMR1, FXR1 and FXR2, were identified to directly and predominantly interact with GDCGG microRNAs through their structurally disordered RGG/RG domains. Preferential association of this protein family with ALS-related microRNAs was confirmed by in vitro binding studies on a transcriptome-wide scale. Immunohistochemistry of lumbar spinal cord revealed aberrant expression level and aggregation of FXR1 and FXR2 in C9orf72- and FUS-linked familial ALS, but also patients with sporadic ALS. Further analysis of ALS autopsies and induced pluripotent stem cell-derived motor neurons with FUS mutations showed co-aggregation of FXR1 with FUS. Hence, our translational approach was able to take advantage of blood microRNAs to reveal CNS pathology, and suggests an involvement of the fragile X-related proteins in familial and sporadic ALS already at a presymptomatic stage. The findings may uncover disease mechanisms relevant to many patients with ALS. They furthermore underscore the systemic, extra-CNS aspect of ALS.
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http://dx.doi.org/10.1093/brain/awab018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105042PMC
May 2021

Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGFβ Signaling.

Neurotherapeutics 2021 Apr 15. Epub 2021 Apr 15.

Department of Neurology, University Hospital Regensburg, Regensburg, Germany.

Adult neurogenesis is a target for brain rejuvenation as well as regeneration in aging and disease. Numerous approaches showed efficacy to elevate neurogenesis in rodents, yet translation into therapies has not been achieved. Here, we introduce a novel human TGFβ-RII (Transforming Growth Factor-Receptor Type II) specific LNA-antisense oligonucleotide ("locked nucleotide acid"-"NVP-13"), which reduces TGFβ-RII expression and downstream receptor signaling in human neuronal precursor cells (ReNcell CX® cells) in vitro. After we injected cynomolgus non-human primates repeatedly i.th. with NVP-13 in a preclinical regulatory 13-week GLP-toxicity program, we could specifically downregulate TGFβ-RII mRNA and protein in vivo. Subsequently, we observed a dose-dependent upregulation of the neurogenic niche activity within the hippocampus and subventricular zone: human neural progenitor cells showed significantly (up to threefold over control) enhanced differentiation and cell numbers. NVP-13 treatment modulated canonical and non-canonical TGFβ pathways, such as MAPK and PI3K, as well as key transcription factors and epigenetic factors involved in stem cell maintenance, such as MEF2A and pFoxO3. The latter are also dysregulated in clinical neurodegeneration, such as amyotrophic lateral sclerosis. Here, we provide for the first time in vitro and in vivo evidence for a novel translatable approach to treat neurodegenerative disorders by modulating neurogenesis.
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http://dx.doi.org/10.1007/s13311-021-01045-2DOI Listing
April 2021

Functional and Molecular Properties of DYT-SGCE Myoclonus-Dystonia Patient-Derived Striatal Medium Spiny Neurons.

Int J Mol Sci 2021 Mar 30;22(7). Epub 2021 Mar 30.

Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

Myoclonus-dystonia (DYT-SGCE, formerly DYT11) is characterized by alcohol-sensitive, myoclonic-like appearance of fast dystonic movements. It is caused by mutations in the gene encoding ε-sarcoglycan leading to a dysfunction of this transmembrane protein, alterations in the cerebello-thalamic pathway and impaired striatal plasticity. To elucidate underlying pathogenic mechanisms, we investigated induced pluripotent stem cell (iPSC)-derived striatal medium spiny neurons (MSNs) from two myoclonus-dystonia patients carrying a heterozygous mutation in the gene (c.298T>G and c.304C>T with protein changes W100G and R102X) in comparison to two matched healthy control lines. Calcium imaging showed significantly elevated basal intracellular Ca content and lower frequency of spontaneous Ca signals in SGCE MSNs. Blocking of voltage-gated Ca channels by verapamil was less efficient in suppressing KCl-induced Ca peaks of SGCE MSNs. Ca amplitudes upon glycine and acetylcholine applications were increased in SGCE MSNs, but not after GABA or glutamate applications. Expression of voltage-gated Ca channels and most ionotropic receptor subunits was not altered. SGCE MSNs showed significantly reduced GABAergic synaptic density. Whole-cell patch-clamp recordings displayed elevated amplitudes of miniature postsynaptic currents and action potentials in SGCE MSNs. Our data contribute to a better understanding of the pathophysiology and the development of novel therapeutic strategies for myoclonus-dystonia.
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http://dx.doi.org/10.3390/ijms22073565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037318PMC
March 2021

Chronic-Progressive Dopaminergic Deficiency Does Not Induce Midbrain Neurogenesis.

Cells 2021 Mar 31;10(4). Epub 2021 Mar 31.

Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany.

Background: Consecutive adult neurogenesis is a well-known phenomenon in the ventricular-subventricular zone of the lateral wall of the lateral ventricles (V-SVZ) and has been controversially discussed in so-called "non-neurogenic" brain areas such as the periventricular regions (PVRs) of the aqueduct and the fourth ventricle. Dopamine is a known modulator of adult neural stem cell (aNSC) proliferation and dopaminergic neurogenesis in the olfactory bulb, though a possible interplay between local dopaminergic neurodegeneration and induction of aNSC proliferation in mid/hindbrain PVRs is currently enigmatic.

Objective/hypothesis: To analyze the influence of chronic-progressive dopaminergic neurodegeneration on both consecutive adult neurogenesis in the PVRs of the V-SVZ and mid/hindbrain aNSCs in two mechanistically different transgenic animal models of Parkinson´s disease (PD).

Methods: We used Thy1-m[A30P]h α synuclein mice and Leu9'Ser hypersensitive α4* nAChR mice to assess the influence of midbrain dopaminergic neuronal loss on neurogenic activity in the PVRs of the V-SVZ, the aqueduct and the fourth ventricle.

Results: In both animal models, overall proliferative activity in the V-SVZ was not altered, though the proportion of B2/activated B1 cells on all proliferating cells was reduced in the V-SVZ in Leu9'Ser hypersensitive α4* nAChR mice. Putative aNSCs in the mid/hindbrain PVRs are known to be quiescent in vivo in healthy controls, and dopaminergic deficiency did not induce proliferative activity in these regions in both disease models.

Conclusions: Our data do not support an activation of endogenous aNSCs in mid/hindbrain PVRs after local dopaminergic neurodegeneration. Spontaneous endogenous regeneration of dopaminergic cell loss through resident aNSCs is therefore unlikely.
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http://dx.doi.org/10.3390/cells10040775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066763PMC
March 2021

A Nation-Wide, Multi-Center Study on the Quality of Life of ALS Patients in Germany.

Brain Sci 2021 Mar 14;11(3). Epub 2021 Mar 14.

Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.

Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = -1.96 per increase of one point in the ALSFRS-R score, < 0.001). "Limb-onset" ALS (ALS) was associated with a better QoL than "bulbar-onset" ALS (ALS) (mean ALSAQ-5 total score 55.46 versus 60.99, = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = -7.60, = 0.001), being tracheostomized (β = -14.80, = 0.004) and using non-invasive ventilation (β = -5.71, = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, = 0.007), and increasing age (β = 0.18, = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care.
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http://dx.doi.org/10.3390/brainsci11030372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998410PMC
March 2021

Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment.

Ann Clin Transl Neurol 2021 05 31;8(5):1049-1063. Epub 2021 Mar 31.

Department of Neurology, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Objective: To determine whether serum creatine kinase activity (CK) and serum creatinine concentration (Crn) are prognostic and predictive biomarkers for disease severity, disease progression, and nusinersen treatment effects in adult patients with 5q-associated spinal muscular atrophy (SMA).

Methods: Within this retrospective, multicenter observational study in 206 adult patients with SMA, we determined clinical subtypes (SMA types, ambulatory ability) and repeatedly measured CK and Crn and examined disease severity scores (Hammersmith Functional Motor Scale Expanded, Revised Upper Limb Module, and revised Amyotrophic Lateral Sclerosis Functional Rating Scale). Patients were followed under nusinersen treatment for 18 months.

Results: CK and Crn differed between clinical subtypes and correlated strongly with disease severity scores (e.g., for Hammersmith Functional Motor Scale Expanded: (CK) ρ = 0.786/ (Crn) ρ = 0.558). During the 18 months of nusinersen treatment, CK decreased (∆CK = -17.56%, p < 0.0001), whereas Crn slightly increased (∆Crn = +4.75%, p < 0.05).

Interpretation: Serum creatine kinase activity and serum creatinine concentration reflect disease severity of spinal muscular atrophy and are promising biomarkers to assess patients with spinal muscular atrophy during disease course and to predict treatment response. The decrease of creatine kinase activity, combined with the tendency of creatinine concentration to increase during nusinersen treatment, suggests reduced muscle mass wasting with improved muscle energy metabolism.
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http://dx.doi.org/10.1002/acn3.51340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108420PMC
May 2021

Cerebellar atrophy on top of motor neuron compromise as indicator of late-onset GM2 gangliosidosis.

J Neurol 2021 Jun 9;268(6):2259-2262. Epub 2021 Mar 9.

Abteilung Neuropädiatrie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

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http://dx.doi.org/10.1007/s00415-021-10492-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179894PMC
June 2021

Treatment satisfaction in 5q-spinal muscular atrophy under nusinersen therapy.

Ther Adv Neurol Disord 2021 5;14:1756286421998902. Epub 2021 Mar 5.

Department of Neurology, Hannover Medical School, Hannover, Germany.

Background: Nusinersen was the first approved disease-modifying therapy for all 5q-spinal muscular atrophy (SMA) patients regardless of age or disease severity. Its efficacy in adults has recently been demonstrated in a large cohort by motor outcome measures, which were only partially suitable to detect changes in very mildly or severely affected patients. Patient-reported outcome measures (PROs) have been suggested as a valuable addition. Here, we aimed to assess treatment satisfaction and investigate whether it may be a useful PRO to monitor SMA patients.

Methods: We enrolled 91 mainly adult 5q-SMA patients treated with nusinersen in a national, multicenter, cross-sectional observational study. 21 patients underwent longitudinal follow up. Patients' satisfaction with treatment in four dimensions (global, effectiveness, convenience, side effects) was assessed by the Treatment Satisfaction Questionnaire for Medication German version 1.4 (TSQM-1.4) and related to clinical parameters, motor scores, and treatment duration.

Results: More than 90% of SMA patients were consistently satisfied over a median treatment duration of 10 months. Highest mean scores were observed in the dimensions 'side effects,' 'global satisfaction,' and 'effectiveness' (93.5 ± 14.8 73.1 ± 21.0 and 64.8 ± 20.6, respectively). Patients' satisfaction with the convenience of treatment was considerably lower (43.6 ± 20.2). Interestingly, satisfaction with the effectiveness was higher in ambulatory ( = 0.014) compared with non-ambulatory patients and directly correlated to motor outcome measures. Five non-ambulatory patients withdrew from therapy. All of them presented with a deterioration of motor outcome measures and reported dissatisfaction with treatment effectiveness and convenience.

Conclusion: Most patients were satisfied with nusinersen treatment effectiveness. Less severely affected patients indicated higher satisfaction. The TSQM-1.4 helped to identify therapy non-responders, who mainly addressed dissatisfaction with effectiveness and convenience. We suggest introducing the TSQM-1.4 as an additional PRO in SMA into clinical practice.
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http://dx.doi.org/10.1177/1756286421998902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940734PMC
March 2021

The ALS-Associated FUS (P525L) Variant Does Not Directly Interfere with Microtubule-Dependent Kinesin-1 Motility.

Int J Mol Sci 2021 Feb 28;22(5). Epub 2021 Feb 28.

Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany.

Deficient intracellular transport is a common pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mutations in the fused-in-sarcoma (FUS) gene are one of the most common genetic causes for familial ALS. Motor neurons carrying a mutation in the nuclear localization sequence of FUS (P525L) show impaired axonal transport of several organelles, suggesting that mislocalized cytoplasmic FUS might directly interfere with the transport machinery. To test this hypothesis, we studied the effect of FUS on kinesin-1 motility . Using a modified microtubule gliding motility assay on surfaces coated with kinesin-1 motor proteins, we showed that neither recombinant wildtype and P525L FUS variants nor lysates from isogenic ALS-patient-specific iPSC-derived spinal motor neurons expressing those FUS variants significantly affected gliding velocities. We hence conclude that during ALS pathogenesis the initial negative effect of FUS (P525L) on axonal transport is an indirect nature and requires additional factors or mechanisms.
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http://dx.doi.org/10.3390/ijms22052422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957795PMC
February 2021

The palmomental reflex in amyotrophic lateral sclerosis - a clinical sign of executive or motor dysfunction?

Amyotroph Lateral Scler Frontotemporal Degener 2021 Mar 3:1-4. Epub 2021 Mar 3.

Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

: The palmomental reflex (PMR) is commonly interpreted as a frontal release sign, but it has also been discussed as a clinical marker of motoneuron affection in amyotrophic lateral sclerosis (ALS). The aim of this study was to investigate the impact of motor dysfunction versus neurocognitive impairment on the appearance of PMR in amyotrophic lateral sclerosis (ALS). : 97 patients with ALS and ALS-variants were enrolled in this prospective, cross-sectional study. PMR was examined in a standardized procedure and the neurocognitive profile was assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Disease severity and motor function were recorded using ALS Functional Rating Scale revised (ALSFRS-R) and standardized clinical assessment. 52% of all patients had a positive PMR (PMR+). These patients showed more frequently signs of motor dysfunction in the bulbar region ( < 0.001), impaired cognitive performance in the ECAS ALS-specific score ( < 0.05), predominantly in executive functions ( < 0.01), as well as lower scores in ALSFRS-R ( < 0.05) compared to patients without PMR (PMR-). A multivariate logistic regression analysis revealed that bulbar involvement, executive function impairment, and a lower motor and respiratory (non-bulbar) ALSFRS-R significantly predicted PMR+ (all  < 0.05), with bulbar involvement being a stronger predictor than executive function impairment. In this study, we showed that bulbar involvement is a much stronger predictor on the appearance of PMR compared to executive function impairment. PMR is therefore primarily a sign for bulbar involvement, rather than a sign for executive dysfunction in ALS patients.
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http://dx.doi.org/10.1080/21678421.2021.1883667DOI Listing
March 2021

Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis.

Life Sci Alliance 2021 04 22;4(4). Epub 2021 Feb 22.

Translational Neurodegeneration Section "Albrecht-Kossel," Department of Neurology, and Center for Transdisciplinary Neuroscience (CTNR), University Medical Center Rostock, University of Rostock, Rostock, Germany

Intronic hexanucleotide repeat expansions (HREs) in are the most frequent genetic cause of amyotrophic lateral sclerosis, a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOFs) through DPRs versus loss of C9ORF72 functions (LOFs). Through multiparametric high-content (HC) live profiling in spinal MNs from induced pluripotent stem cells and comparison to mutant FUS and TDP43, we show that HRE caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA double-strand breaks (DSBs), RNA foci, DPRs, and apoptosis. We show that both GOFs and LOFs were necessary to yield the overall pathology. Increased RNA foci and DPRs concurred with onset of axon trafficking defects, DSBs, and cell death, although DSB induction itself did not phenocopy C9ORF72 mutants. Interestingly, the majority of LOF-specific DEGs were shared with HRE-mediated GOF DEGs. Finally, C9ORF72 LOF was sufficient-albeit to a smaller extent-to induce premature distal axonal trafficking deficits and increased DSBs.
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http://dx.doi.org/10.26508/lsa.202000764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918691PMC
April 2021

Impairment of mitochondrial oxidative phosphorylation in skin fibroblasts of SALS and FALS patients is rescued by in vitro treatment with ROS scavengers.

Exp Neurol 2021 May 23;339:113620. Epub 2021 Jan 23.

Institute of Experimental Epileptology and Cognition Research, Life & Brain Center, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.

Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressive, neurodegenerative disorder affecting upper and lower motor neurons. Approximately 10% of patients suffer from familial ALS (FALS) with mutations in different ubiquitously expressed genes including SOD1, C9ORF72, TARDBP, and FUS. There is compelling evidence for mitochondrial involvement in the pathogenic mechanisms of FALS and sporadic ALS (SALS), which is believed to be relevant for disease. Owing to the ubiquitous expression of relevant disease-associated genes, mitochondrial dysfunction is also detectable in peripheral patient tissue. We here report results of a detailed investigation of the functional impairment of mitochondrial oxidative phosphorylation (OXPHOS) in cultured skin fibroblasts from 23 SALS and 17 FALS patients, harboring pathogenic mutations in SOD1, C9ORF72, TARDBP and FUS. A considerable functional and structural mitochondrial impairment was detectable in fibroblasts from patients with SALS. Similarly, fibroblasts from patients with FALS, harboring pathogenic mutations in TARDBP, FUS and SOD1, showed mitochondrial defects, while fibroblasts from C9ORF72 associated FALS showed a very mild impairment detectable in mitochondrial ATP production rates only. While we could not detect alterations in the mtDNA copy number in the SALS or FALS fibroblast cultures, the impairment of OXPHOS in SALS fibroblasts and SOD1 or TARDBP FALS could be rescued by in vitro treatments with CoQ (5 μM for 3 weeks) or Trolox (300 μM for 5 days). This underlines the role of elevated oxidative stress as a potential cause for the observed functional effects on mitochondria, which might be relevant disease modifying factors.
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http://dx.doi.org/10.1016/j.expneurol.2021.113620DOI Listing
May 2021

Ionic Phases of Ammonia-Rich Hydrate at High Densities.

Phys Rev Lett 2021 Jan;126(1):015702

Key Laboratory of Materials Physics, Institute of Solid State Physics, HFIPS, Chinese Academy of Sciences, Hefei 230031, China.

Mixtures of ammonia and water are major components of the "hot ice" mantle regions of icy planets. The ammonia-rich ammonia hemihydrate (AHH) plays a pivotal role as it precipitates from water-rich mixtures under pressure. It has been predicted to form ionic high-pressure structures, with fully disintegrated water molecules. Utilizing Raman spectroscopy measurements up to 123 GPa and first-principles calculations, we report the spontaneous ionization of AHH under compression. Spectroscopic measurements reveal that molecular AHH begins to transform into an ionic state at 26 GPa and then above ∼69  GPa transforms into the fully ionic P3[over ¯]m1 phase, AHH-III, characterized as ammonium oxide (NH_{4}^{+})_{2}O^{2-}.
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http://dx.doi.org/10.1103/PhysRevLett.126.015702DOI Listing
January 2021

FUS Is Not Mislocalized in Spinal Motor Neurons Derived From Human Induced Pluripotent Stem Cells of Main Non-FUS ALS Subtypes.

J Neuropathol Exp Neurol 2021 Jan 15. Epub 2021 Jan 15.

Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany.

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http://dx.doi.org/10.1093/jnen/nlaa154DOI Listing
January 2021

Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Niemann-Pick Type C1.

Int J Mol Sci 2021 Jan 12;22(2). Epub 2021 Jan 12.

Translational Neurodegeneration Section "Albrecht Kossel", Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany.

The lysosomal storage disorders Niemann-Pick disease Type C1 (NPC1) and Type C2 (NPC2) are rare diseases caused by mutations in the or gene. Both NPC1 and NPC2 are proteins responsible for the exit of cholesterol from late endosomes and lysosomes (LE/LY). Consequently, mutations in one of the two proteins lead to the accumulation of unesterified cholesterol and glycosphingolipids in LE/LY, displaying a disease hallmark. A total of 95% of cases are due to a deficiency of NPC1 and only 5% are caused by NPC2 deficiency. Clinical manifestations include neurological symptoms and systemic symptoms, such as hepatosplenomegaly and pulmonary manifestations, the latter being particularly pronounced in NPC2 patients. NPC1 and NPC2 are rare diseases with the described neurovisceral clinical picture, but studies with human primary patient-derived neurons and hepatocytes are hardly feasible. Obviously, induced pluripotent stem cells (iPSCs) and their derivatives are an excellent alternative for indispensable studies with these affected cell types to study the multisystemic disease NPC1. Here, we present a review focusing on studies that have used iPSCs for disease modeling and drug discovery in NPC1 and draw a comparison to commonly used NPC1 models.
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http://dx.doi.org/10.3390/ijms22020710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828283PMC
January 2021