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Transcriptional dysregulation in the spinal cord of SCA3 provides insights into disease mechanisms [Human_RNAseq]

ABSTRACT: Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by polyglutamine repeat expansion in the ATXN3 gene. Despite the ubiquitous expression of ATXN3 throughout the body, SCA3 pathology is pronounced in select, vulnerable regions within the central nervous system (CNS). Notably, imaging studies of SCA3 patients have revealed spinal cord atrophy prior to ataxia symptom onset and progressing with disease severity. However, the molecular mechanisms underlying SCA3 pathology in the spinal cord remain largely unexplored. Here, we present, for the first time, a comprehensive analysis of the spinal cord transcriptome using SCA3 tissue from humans and mouse models. Our data demonstrates both early and progressive transcriptional dysregulation in the spinal cord, impacting key biological processes such as lipid metabolism, inflammation, cellular structure, and nucleic acid processing. Transcriptomic profiling of Atxn3 knockout mice revealed only weak transcriptional changes in the spinal cord, with minimal overlap compared to the robust alterations observed in SCA3 knock-in mice, indicating that the molecular signature of the disease in the spinal cord is likely not driven by ATXN3 loss of function. In addition, we identified aberrant RNA splicing, particularly affecting genes involved in cytoskeletal organization. Collectively, our findings indicate that SCA3-associated transcriptional dysregulation in the spinal cord contributes to canonical pathological mechanisms of SCA3 both early and progressively. These results underscore the central role of the spinal cord in SCA3 pathogenesis and advocate for its inclusion as a key therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309548 | GEO | 2025/10/29

REPOSITORIES: GEO

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Project description:Spinocerebellar ataxia type 3 (SCA3/MJD) has a polyQ etiology but, the current knowledge on molecular processes and proteins involved in pathogenesis is insufficient. Due to its proteolytic function, Ataxin-3 can influence other proteins, yet the global picture of crucial proteins and pathways in SCA3 was not investigated previously. Here, we explored molecular SCA3 mechanism by interdisciplinary research paradigm combining SCA3 knock-in model, behavior, MRI, brain proteomics, precise axonal proteomics, neuronal energy recordings, labeling of vesicles, and inclusions and focusing in axonal compartment. Using the global proteomics, we found dysregulation of protein homeostasis over the entire disease progression. The early SCA3 phase was associated with reduced body weight gain, the presence of the number of dysregulated proteins related to metabolism and mitochondria, and an altered profile of oxygen consumption rate in neurons. Moreover, the early phase presented alterations of protein metabolism, cytoskeletal architecture, axonal and synaptic proteins. Protein dysregulations indicated that the compartment involved in SCA3 pathogenesis next to the mitochondria are also neuronal processes and axons in particular. To confirm that the axon is one of the central compartments in SCA3 pathogenesis, we performed targeted proteomics on axons and somatodendritic compartments. We revealed highly increased axonal localization of protein synthesis machinery, including ribosomes, translation factors, and RNA binding proteins, while the level of proteins responsible for cellular transport and mitochondria was decreased. In summary, the SCA3 disease mechanism is based on the broad influence of mutant ataxin-3 on the neuronal proteome. Processes central in our SCA3 model include disturbed localization of proteins between axonal and somatodendritic compartment, early neuronal energy deficit, altered neuronal cytoskeletal structure, an overabundance of protein synthetic machinery in axons.

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Transcriptional dysregulation in the spinal cord of SCA3 provides insights into disease mechanisms [Human_RNAseq]

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