A5102780190- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- DNA Repair Mechanisms
- Neurological disorders and treatments
- Parkinson's Disease Mechanisms and Treatments
- RNA Research and Splicing
- Ubiquitin and proteasome pathways
- Hereditary Neurological Disorders
- Amyotrophic Lateral Sclerosis Research
- Calpain Protease Function and Regulation
- Neurological diseases and metabolism
- Metabolism and Genetic Disorders
- RNA regulation and disease
- Autophagy in Disease and Therapy
- Cerebrovascular and genetic disorders
- CRISPR and Genetic Engineering
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Connective tissue disorders research
- SARS-CoV-2 and COVID-19 Research
- Restless Legs Syndrome Research
- Platelet Disorders and Treatments
- Endoplasmic Reticulum Stress and Disease
- vaccines and immunoinformatics approaches
- Nuclear Structure and Function
- Microtubule and mitosis dynamics
University of Tübingen
2014-2024
University Hospital Bonn
2023
ZB MED - Information Centre for Life Sciences
2023
Max Delbrück Center
2023
Charité - Universitätsmedizin Berlin
2023
Hôpital Gui de Chauliac
2023
Universitätsklinikum Tübingen
2021-2022
Bernstein Center for Computational Neuroscience Tübingen
2018
Bethesda University
2008
University of Aberdeen
2007
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited neurodegenerative disorder caused by the expansion of a CAG repeat in MJD1 gene resulting expanded polyglutamine ataxin-3 protein. To study course disease, we generated transgenic mice for SCA3 using full-length constructs containing 15, 70, or 148 repeats, respectively. Control (15 CAGs) were phenotypically normal and had no neuropathological findings. However, with repeats severely affected strong neurological...
Article8 June 2020Open Access Source DataTransparent process Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage humans mice Carlo Wilke orcid.org/0000-0002-7250-8597 Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University Tübingen, Germany German Neurodegenerative Diseases (DZNE), Search more papers by this author Eva Haas Medical Genetics Applied Genomics, Centre Rare Diseases, Kathrin Reetz Department RWTH Aachen...
Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures.To evaluate total tau (t-tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and neurofilament light-chain (NfL) fluid SCA3, ATXN3 mutation carriers (n = 143) controls 172) were clinically assessed, the plasma concentrations of four proteins analysed on Simoa HD-1 platform. Eleven carrier cerebrospinal samples t-tau phosphorylated (p-tau181 )....
Spinocerebellar ataxia type 3 (SCA3) is pathologically characterized by the formation of intranuclear aggregates which contain ataxin-3, mutated protein in SCA3, a specific subtype neurons. It has been proposed that ataxin-3 cleaved proteolytic enzymes, particular calpains and caspases, eventually leading to aggregates. In our study, we examined ability cleave vitro vivo. We demonstrated cell culture mouse brain homogenates cleavage overexpressed calpain-2 occur polyglutamine expanded more...
Spinocerebellar ataxia type 3 (SCA3), or Machado-Joseph disease (MJD), is a progressive neurodegenerative disorder caused by CAG expansion in the ATXN3 gene. The expanded repeat translated into prolonged polyglutamine ataxin-3 protein and accumulates within inclusions, acquiring toxic properties, which results degeneration of cerebellum brain stem. In current study, non-allele-specific silencing approach was investigated using artificial microRNAs engineered to target various regions gene...
Abstract Background Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited adult-onset disease. We aimed to describe longitudinal changes in clinical and biological findings identify predictors for progression. Methods used data from participants enrolled the ESMI cohort collected between Nov 09, 2016 July 18, 2023. The freeze included 14 sites five European countries United States. assessed with Scale Assessment Rating of Ataxia (SARA). measured disease-specific mutant...
Background: Spinocerebellar ataxia type 3 (SCA3) is one of the most common dominantly inherited worldwide. Despite research advances, no approved disease-modifying treatment exists, and management focuses on symptom alleviation functional capacity maximization. Symptomatic guidelines are scarce, leaving decisions to physicians' discretion. The lack studies SCA3 hinders therapy standardization. This study investigated medication usage patterns among mutation carriers controls recruited by...
Familial thrombosis (FT) has been described as a rare autosomal-dominant disorder, mostly caused by activating mutations of the thrombopoietin gene (THPO). Other cases FT have linked to one two different germline in myeloproliferative leukaemia virus oncogene (MPL), which codes for receptor MPL. We studied an Arab family with siblings severe thrombocytosis linkage analysis and obtained evidence Sequencing revealed homozygosity novel MPL mutation p.Pro106Leu (c.317C > T) siblings....
Mutant ataxin-3 is aberrantly folded and proteolytically cleaved in spinocerebellar ataxia type 3. The C-terminal region of the protein includes a polyglutamine stretch that expanded Here, we report on analysis an mutant mouse has been obtained by gene trap integration. fusion encompasses 259 N-terminal amino acids including Josephin domain ubiquitin-interacting motif but lacks C-terminus with stretch, valosin-containing binding part 2. Homozygous mice were viable showed no apparent...
Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited worldwide, caused by a CAG repeat expansion in Ataxin-3 gene resulting polyglutamine (polyQ)-expansion corresponding protein. The disease characterized neuropathological, phenotypical, and specific transcriptional changes affected brain regions. So far, there no mouse model available representing all different aspects of disease, yet highly needed for better understanding pathomechanisms. Here, we novel knock-in...
Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by CAG repeat expansion in the ataxin-3 gene. Although no curative therapy yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are critical importance as pharmacodynamic particularly target engagement markers.We aimed at developing an ultrasensitive...
Abstract Background Disease severity in spinocerebellar ataxia type 3 (SCA3) is commonly defined by the Scale for Assessment and Rating of Ataxia (SARA) sum score, but little known about contributions progression patterns individual items. Objectives To investigate temporal dynamics SARA item scores SCA3 patients evaluate if clinical demographic factors are differentially associated with evolution axial appendicular ataxia. Methods In a prospective, multinational cohort study involving 11...
Ataxin-3, the disease protein in Machado-Joseph disease, is known to be proteolytically modified by various enzymes including two major families of proteases, caspases and calpains. This processing results generation toxic fragments polyglutamine-expanded protein. Although approaches were undertaken identify cleavage sites within ataxin-3 evaluate impact on molecular pathogenesis calpain-mediated localization remained unclear. Here, we report first precise calpain characterization resulting...
Alterations in mitochondrial morphology and function have been linked to neurodegenerative diseases, including Parkinson disease, Alzheimer disease Huntington disease. Metabolic defects, resulting from dysfunctional mitochondria, reported patients respective animal models of all those diseases. Spinocerebellar Ataxia Type 3 (SCA3), another disorder, also presents with metabolic defects loss body weight early stages although the possible role dysfunction SCA3 pathology is still be determined....
Dysfunctional mitochondria are linked to several neurodegenerative diseases. Metabolic defects, a symptom which can result from dysfunctional mitochondria, also present in spinocerebellar ataxia type 3 (SCA3), known as Machado-Joseph disease, the most frequent, dominantly inherited worldwide. Mitochondrial dysfunction has been reported for disorders and ataxin-3 is deubiquitinylate parkin, key protein required canonical mitophagy. In this study, we analyzed mitochondrial function mitophagy...
Spinocerebellar ataxia type 3/Machado-Joseph disease is the most common autosomal dominant ataxia. In view of development targeted therapies, knowledge early biomarker changes needed. We analyzed cross-sectional data 292 spinocerebellar mutation carriers. Blood concentrations mutant ATXN3 were high before and after onset, whereas neurofilament light deviated from normal 13.3 years onset. Pons cerebellar white matter volumes decreased 2.2 0.6 propose a staging model that includes stage...
Abstract Spinocerebellar ataxia type 3 ( SCA 3) is an autosomal dominantly inherited neurodegenerative disorder for which no curative therapy available. The cause of this disease the expansion a CAG repeat in so‐called ATXN gene leading to expanded polyglutamine stretch ataxin‐3 protein. Although function has been defined as deubiquitinating enzyme, pathogenic pathway underlying remains be deciphered. Besides others, also glutamatergic system seems altered 3. antiglutamatergic substance...
Hereditary spastic paraplegia type 5 is a neurodegenerative disease caused by loss-of-function mutations in the CYP7B1 gene encoding oxysterol 7-α-hydroxylase involved bile acid synthesis liver. Lack of leads to an accumulation its substrates, particular 25-hydroxycholesterol and 27-hydroxycholesterol that are able cross blood-brain barrier have neurotoxic properties. A potential therapeutic strategy for SPG5 replacement administration mRNA. Here, we studied intravenous application...
Spinocerebellar ataxia type 3 (SCA3) is caused by an expanded polyglutamine stretch in ataxin-3. While wild-type ataxin-3 has important functions, e.g., as a deubiquitinase, downregulation of mutant likely to slow down the course this fatal disease. We established screening platform with human neurons patients and controls derived from induced pluripotent stem cells test antisense oligonucleotides (ASOs) for their effects on expression. identified ASO that suppressed levels >90% after...
Transcriptional dysregulation has been described in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), an autosomal dominant caused by a polyglutamine expansion the ataxin-3 protein. As is ubiquitously expressed, transcriptional alterations blood may reflect early changes that start before clinical onset and might serve as peripheral biomarkers research settings. Our goal was to describe enriched pathways report dysregulated genes, which can track onset, severity or progression...
Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is a heritable proteinopathy disorder, whose causative gene, ATXN3, undergoes alternative splicing. Ataxin-3 protein isoforms differ in their toxicity, suggesting that certain ATXN3 splice variants may be crucial driving the selective toxicity SCA3. Using RNA-seq datasets we identified and determined abundance of annotated transcripts blood (n = 60) cerebellum 12) SCA3 subjects controls. The reference transcript (ATXN3–251),...
Abstract In view of upcoming clinical trials, quantitative molecular markers accessible in peripheral blood are critical importance as prognostic or pharmacodynamic genetic neurodegenerative diseases such Spinocerebellar Ataxia Type 3 (SCA3), particular for signaling target engagement. this pilot study, we focused on the quantification ataxin-3, protein altered SCA3, human mononuclear cells (PBMCs) acquired from preataxic and ataxic SCA3 mutation carriers well healthy controls, a marker...
Abstract Background Non-motor symptoms (NMS) are a substantial burden for patients with SCA3. There limited data on their frequency, and relation disease severity activities of daily living is not clear. In addition, lifestyle may either influence or be affected by the occurrence NMS. Objective To characterize NMS in SCA3 investigate possible associations factors. Methods prospective cohort study, we performed cross-sectional analysis 227 patients, 42 pre-ataxic mutation carriers, 112...