Work

Transcriptomic and neurotransmitter correlates of structure and function spatial variations patterns in spinocerebellar Ataxia

Year: 2025

Type: article

Abstract: Spinocerebellar ataxia (SCA) is characterized by cortical structural and functional impairments, but the underlying biological mechanisms remain poorly understood. We applied T1-weighted magnetic resonance imaging (MRI) and resting-state functional MRI (fMRI) to investigate cortical alterations in 49 SCA patients and 48 matched controls. Cortical thickness and amplitude of low-frequency fluctuations (ALFF) were quantified and compared with spatial maps of 19 neurotransmitter systems. Gene expression patterns were examined using partial least squares regression, followed by gene ontology analysis to identify associated biological processes. Both cortical thickness and ALFF emerged as sensitive biomarkers of cortical impairment in SCA. Thickness alterations were strongly associated with disruptions in cholinergic, serotonergic, and glutamatergic systems. ALFF alterations were linked to toxin-response and detoxification processes, with relevant gene expression enriched in astrocytes. Our convergent imaging–transcriptomic analysis integrates direct molecular vulnerability and CTC-based transsynaptic degeneration, yielding a unified systems-level view of SCA. These findings go beyond correlation by prioritizing molecular pathways and non-neuronal cellular targets and enabling network-informed prediction of additional vulnerable regions. • Cortical thinning and altered amplitude of low-frequency fluctuations (ALFF) characterize structural and functional abnormalities in SCA, primarily affecting the sensorimotor network and correlating with disease severity. • Cortical thickness variations co-localize with multiple neurotransmitter systems, including dopamine, serotonin, and glutamate receptors, suggesting their involvement in cortical degeneration in SCA. • ALFF alterations are strongly associated with gene expression patterns, with enrichment in pathways related to neurodevelopment and toxin clearance, as identified through partial least squares (PLS) regression analysis. • Astrocytes and pericytes emerge as key cellular contributors to ALFF changes, highlighting the role of neuroinflammation and blood-brain barrier dysfunction in SCA pathology.

Source: Neurobiology of Disease

DOI: 10.1016/j.nbd.2025.107228