Abstract

Spinocerebellar ataxia type 3 (SCA3/MJD) is caused by CAG expansion mutation resulting in a long polyQ domain in mutant ataxin-3. The mutant protein is a special type of protease, deubiquitinase, which may indicate its prominent impact on the regulation of cellular proteins levels and activity. Yet, the global model picture of SCA3 disease progression on the protein level, molecular pathways in the brain, and neurons, is largely unknown. Here, we investigated the molecular SCA3 mechanism using an interdisciplinary research paradigm combining behavioral and molecular aspects of SCA3 in the knock-in ki91 model. We used the behavior, brain magnetic resonance imaging (MRI) and brain tissue examination to correlate the disease stages with brain proteomics, precise axonal proteomics, neuronal energy recordings, and labeling of vesicles. We have demonstrated that altered metabolic and mitochondrial proteins in the brain and the lack of weight gain in Ki91 SCA3/MJD mice is reflected by the failure of energy metabolism recorded in neonatal SCA3 cerebellar neurons. We have determined that further, during disease progression, proteins responsible for metabolism, cytoskeletal architecture, vesicular, and axonal transport are disturbed, revealing axons as one of the essential cell compartments in SCA3 pathogenesis. Therefore we focus on SCA3 pathogenesis in axonal and somatodendritic compartments revealing 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. We demonstrate the accumulation of axonal vesicles in neonatal SCA3 cerebellar neurons and increased phosphorylation of SMI-312 positive adult cerebellar axons, which indicate axonal dysfunction in SCA3. 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 various components of protein synthesis machinery in axons.

Highlights

  • Spinocerebellar ataxia type 3 (SCA3), known as Machado– Joseph disease (MJD), is a neurodegenerative, late-onset, genetic disorder caused by the expansion of CAG repeats in the coding region of the ATXN3 gene (>50 in patients) (McLoughlin et al, 2020)

  • We recently demonstrated that gross transcriptional changes are absent in the pre-symptomatic SCA3 brain of the Ki91 mouse model; dysregulations of proteins and phosphoproteins occurred in these animals, pointing at protein homeostasis as a more general and early trait in disease pathogenesis (Switonski et al, 2015; Wiatr et al, 2019)

  • We demonstrate that the consensus processes identified in the SCA3 Ki91 brains show their functional signs in the primary presymptomatic neurons, and may be the first steps of pathogenesis

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Summary

Introduction

Spinocerebellar ataxia type 3 (SCA3), known as Machado– Joseph disease (MJD), is a neurodegenerative, late-onset, genetic disorder caused by the expansion of CAG repeats in the coding region of the ATXN3 gene (>50 in patients) (McLoughlin et al, 2020). This mutation leads to an expanded polyglutamine (polyQ) tract in the ataxin-3 protein, causing a toxic gain of function (Orr and Zoghbi, 2007). Several lines of evidence point to the disruption of axon organization and, connections between brain structures as one of the main traits in SCA3 pathogenesis (de Rezende et al, 2015; Farrar et al, 2016; Lu et al, 2017). We recently demonstrated that gross transcriptional changes are absent in the pre-symptomatic SCA3 brain of the Ki91 mouse model; dysregulations of proteins and phosphoproteins occurred in these animals, pointing at protein homeostasis as a more general and early trait in disease pathogenesis (Switonski et al, 2015; Wiatr et al, 2019)

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