Biology subjects

Paulson, H.

Publications and source records attributed to Paulson, H..

4 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↗

bioRxiv2021

Impaired oligodendrocyte maturation is an early feature in SCA3 disease pathogenesis

Spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited ataxia, is a polyglutamine neurodegenerative disease for which there is no disease-modifying therapy. The polyglutamine-encoding CAG repeat expansion in the ATXN3 gene results in expression of a mutant form of the ATXN3 protein, a deubiquitinase that causes selective neurodegeneration despite being widely expressed. The mechanisms driving neurodegeneration in SCA3 are unclear. Research to date, however, has focused almost exclusively on neurons. Here, using equal male and female age-matched transgenic mice expressing full-length human mutant ATXN3, we identified early and robust transcriptional changes in selectively vulnerable brain regions that implicate oligodendrocytes in disease pathogenesis. We mapped transcriptional changes across early, mid, and late stages of disease in two selectively vulnerable brain regions, the cerebellum and brainstem. The most significant disease-associated module through weighted gene co-expression network analysis revealed dysfunction in SCA3 oligodendrocyte maturation. These results reflect a toxic gain of function mechanism, as ATXN3 knockout mice do not exhibit any impairments in oligodendrocyte maturation. Genetic crosses to reporter mice revealed a marked reduction in mature oligodendrocytes in SCA3-disease vulnerable brain regions and ultrastructural microscopy confirmed abnormalities in axonal myelination. Further study of isolated oligodendrocyte precursor cells from SCA3 mice established that this impairment in oligodendrocyte maturation is a cell autonomous process. We conclude that SCA3 is not simply a disease of neurons and the search for therapeutic strategies and disease biomarkers will need to account for non-neuronal involvement in SCA3 pathogenesis. SIGNIFICANCE STATEMENTDespite advances in SCA3 disease understanding, much remains unknown about how the disease gene causes brain dysfunction ultimately leading to cell death. We completed a longitudinal transcriptomic analysis of vulnerable brain regions in SCA3 mice to define the earliest and most robust changes across disease progression. Through gene network analyses followed up with biochemical and histological studies in SCA3 mice, we provide evidence for severe dysfunction in oligodendrocyte maturation early in SCA3 pathogenesis. Our results advance understanding of SCA3 disease mechanisms, identify additional routes for therapeutic intervention, and may provide broader insight into polyglutamine diseases beyond SCA3.

neuroscience↗

bioRxiv2021

RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control

The brain expressed ubiquilins (UBQLNs) 1, 2 and 4 are a family of ubiquitin adaptor proteins that participate broadly in protein quality control (PQC) pathways, including the ubiquitin proteasome system (UPS). One family member, UBQLN2, has been implicated in numerous neurodegenerative diseases including ALS/FTD. UBQLN2 typically resides in the cytoplasm but in disease can translocate to the nucleus, as in Huntingtons disease where it promotes the clearance of mutant Huntingtin protein. How UBQLN2 translocates to the nucleus and clears aberrant nuclear proteins, however, is not well understood. In a mass spectrometry screen to discover UBQLN2 interactors, we identified a family of small (13 kDa), highly homologous uncharacterized proteins, RTL8, and confirmed the interaction between UBQLN2 and RTL8 both in vitro using recombinant proteins and in vivo using mouse brain tissue. Under endogenous and overexpressed conditions, RTL8 localizes to nucleoli. When co-expressed with UBQLN2, RTL8 promotes nuclear translocation of UBQLN2. UBQLN2 and RTL8 colocalize within ubiquitin-enriched subnuclear structures containing PQC components. The robust effect of RTL8 on the nuclear translocation and subnuclear localization of UBQLN2 does not extend to the other brain-expressed ubiquilins, UBQLN1 and UBQLN4. Moreover, compared to UBQLN1 and UBQLN4, UBQLN2 preferentially stabilizes RTL8 levels in human cell lines and in mouse brain, supporting functional heterogeneity among UBQLNs. As a novel UBQLN2 interactor that recruits UBQLN2 to specific nuclear compartments, RTL8 may regulate UBQLN2 function in nuclear protein quality control.

neuroscience↗

bioRxiv2019

Ataxin-3 links NOD2 and TLR2 mediated innate immune sensing and metabolism in myeloid cells

The interplay between NOD2 and TLR2 following recognition of components of the bacterial cell wall peptidoglycan is well established, however their role in redirecting metabolic pathways in myeloid cells to degrade pathogens and mount antigen presentation remains unclear. We show NOD2 and TLR2 mediate phosphorylation of the deubiquitinase ataxin-3 via RIPK2 and TBK1. In myeloid cells ataxin-3 associates with the mitochondrial cristae protein MIC60, and is required for oxidative phosphorylation. Depletion of ataxin-3 leads to impaired induction of mitochondrial reactive oxygen species (mROS) and defective bacterial killing. A mass spectrometry analysis of NOD2/TLR2 triggered ataxin-3 deubiquitination targets revealed immunometabolic regulators, including HIF-1 and LAMTOR1 that may contribute to these effects. Thus, we define how ataxin-3 plays an essential role in NOD2 and TLR2 sensing and effector functions in myeloid cells.\n\nSignificance StatementIn recent years it has become clear that cross-talk between metabolic and immune pathways is central to the regulation of host defence. This interplay appears of particular importance in myeloid cells including dendritic cells and macrophages, but it is unclear how two of their key bacterial sensors NOD2 and TLR2 influence metabolism. Here, we define how NOD2/TLR2 signal in myeloid cells to drive optimal mitochondrial functioning required for bacterial destruction. We uncover a new role for Ataxin-3, a deubiquitinase required for non-selective autophagy, in this pathway. We provide a non-biased analysis of Ataxin-3 targets generating evidence for a role in deubiquitination of metabolic mediators during myeloid cell differentiation that will provide an important basis for further study.

immunology↗