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RNA sequencing of a Spinocerebellar ataxia type 3 (SCA3) mouse model containing the full human ATXN3 gene with a repeat expansion of 75-80 CAGs I

ABSTRACT: We have performed RNA sequencing analysis of brain tissue and blood from the MJD84.2 mouse model for SCA3 (described by Cemal et al, Human molecular genetics 2002, 11:1075-1094). Mice were 17.5 months of age at sacrifice and brainstem, cerebellum, cortex and striatum were sequenced. Transgenic SCA3 mice showed most transcriptional changes in striatum and brainstem. Axon guidance, synaptic transmission, pi-3k cascade and cholesterol biosynthesis pathways are implicated to be affected based on the transcriptional changes.

ORGANISM(S): Mus musculus

PROVIDER: GSE107958 | GEO | 2017/12/13

SECONDARY ACCESSION(S): PRJNA422042

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.

Dataset Information

RNA sequencing of a Spinocerebellar ataxia type 3 (SCA3) mouse model containing the full human ATXN3 gene with a repeat expansion of 75-80 CAGs I

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