Biology subjects

Klockgether, T.

Publications and source records attributed to Klockgether, T..

3 recordsLinked to original sources

bioRxiv2025

A Core Pattern of Cerebellar and Brainstem Degeneration and Reduced Cerebrocerebellar Structural Covariance in Spinocerebellar Ataxia Type 3 (SCA3): MRI Volumetrics from ENIGMA-Ataxia

ObjectiveSpinocerebellar ataxia type 3 (SCA3) is a rare, inherited neurodegenerative disease. Here, we profile the spatial spread of atrophy across the whole brain, determine whether brain degeneration preferentially maps onto specific functional networks, and investigate the relationship between cerebellar and cerebral anatomical changes. MethodsWhole-brain grey and white matter (GM and WM) voxel-based morphometry was performed on 408 individuals with SCA3 (82 pre-ataxic) and 293 controls. The SCA3 cohort was stratified by ataxia severity to investigate disease progression, with cerebellar GM atrophy mapped onto a task-based functional atlas. Volume was correlated with disease duration and intensity. Cerebrocerebellar volumetric covariance was assessed to determine whether atrophy was coupled between infra- and supratentorial regions. ResultsThe pattern of atrophy is spatially consistent but progressive in magnitude across the disease course. The greatest atrophy was found in the pons, cerebellar WM, and cerebellar peduncles; correlations with disease severity and duration were also strongest in these regions. Cerebellar GM atrophy was greatest in functional regions associated with motor execution and planning, attention, and emotional processing. Sparse cerebral cortical atrophy appears only in the most severe disease subgroup, while striatal atrophy begins in the earliest stages. Reduced cerebrocerebellar structural covariance is observed in SCA3 participants versus controls. InterpretationWhile cerebellar and brainstem atrophy become more severe, the pattern of atrophy remains largely consistent as SCA3 progresses. Cerebellar GM degeneration occurs in regions associated with motor, cognitive, and affective control, in line with clinical presentation. Cerebellar atrophy is not directly mirrored by cerebral changes.

neuroscience↗

bioRxiv2024

Small non-coding RNA content in plasma-derived extracellular vesicles distinguish ataxic SCA3 mutation carriers from pre-ataxic and control subjects

Spinocerebellar ataxia type 3 (SCA3), a neurodegenerative disorder caused by a CAG expansion in the ATXN3 gene, is the most common spinocerebellar ataxia subtype worldwide. Currently, there is no therapy to stop or prevent disease progression. Promising therapeutic strategies are emerging, but their translation into clinical practice requires sensitive and reliable biomarkers. Blood circulating extracellular vesicles constitute a promising source of biomarkers with potential to track alterations of the central nervous system due to their ability to cross the blood brain barrier. Here, we perform sequencing analysis of small RNAs from plasma-derived extracellular vesicles from SCA3 mutation carriers (10 pre-ataxic and 10 ataxic) and 12 control subjects to identify potential RNA biomarker candidates for this disease. Data showed that plasma-derived extracellular vesicles from ataxic SCA3 mutation carriers are enriched in mitochondrial, nuclear, and nucleolar RNA biotypes compared to pre-ataxic and control subjects. Moreover, ataxic mutation carriers could be discriminated from control and pre-ataxic subjects based on the miRNAs or piRNAs content, but not tRNA. Furthermore, we identified a subset of differentially expressed miRNAs and piRNAs that clearly differentiate ataxic mutation carriers from pre-ataxic and control subjects. These findings open new avenues for further investigation on the role of these RNAs in the pathogenesis of SCA3 and their potential as biomarkers for this disease.

neuroscience↗

bioRxiv2023

Blood and cerebellar abundance of ATXN3 splice variants in spinocerebellar ataxia type 3/Machado-Joseph disease

BackgroundSpinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is an autosomal dominant polyglutamine disease. SCA3/MJD causative gene, ATXN3, is known to undergo alternative splicing (AS) and 54 transcripts are currently annotated. Differences in the toxicity of ataxin-3 protein isoforms, harbouring on its C-terminus two or three ubiquitin interacting motifs (UIMs), were previously uncovered, raising the hypothesis that specific ATXN3 splice variants play key roles in promoting the selective toxicity displayed in SCA3/MJD. MethodsUsing RNA-seq datasets we identified and determined the abundance of annotated ATXN3 transcripts in blood (n=60) and cerebellum (n=12) of SCA3/MJD subjects and controls. ResultsGlobally, the number and the abundance of individual ATXN3 transcripts were higher in the cerebellum than in the blood. While the most abundant transcript in the cerebellum was a protein with a coding sequence not defined of unknown function (ATXN3-208), the transcript with the highest abundance in blood was the reference transcript (ATXN3-251) which translates into an ataxin-3 isoform harboring three UIMs. Noteworthy, the abundance of ATXN3-251 and ATXN3-214, two out of the four transcripts that encode full-length ataxin-3 protein isoforms but differ in the C-terminus were strongly related with tissue expression specificity: ATXN3-251 (3UIM) was expressed in blood 50-fold more than in cerebellum, whereas ATXN3-214 (2UIM) was expressed in the cerebellum 20-fold more than in blood. ConclusionsThese findings provide new insights into the elucidation of ATXN3 AS in different tissues, contributing for a better understanding of SCA3/MJD pathogenesis and providing information for the development of future effective ATXN3 mRNA-lowering therapies.

genetics↗