Motor and Cerebellar Architectural Abnormalities during the Early Progression of Ataxia in a Mouse Model of SCA1 and How Early Prevention Leads to a Better Outcome Later in Life.

Mohamed F Ibrahim,Ruth M Empson,Kay Potapov,Emmet M Power

doi:10.3389/fncel.2017.00292

Abstract

Exposing developing cerebellar Purkinje neurons (PNs) to mutant Ataxin1 (ATXN1) in 82Q spinocerebellar ataxia type 1 (SCA1) mice disrupts motor behavior and cerebellar climbing fiber (CF) architecture from as early as 4 weeks of age. In contrast, if mutant ATXN1 expression is silenced until after cerebellar development is complete, then its impact on motor behavior and cerebellar architecture is greatly reduced. Under these conditions even 6 month old SCA1 mice exhibit largely intact motor behavior and molecular layer (ML) and CF architecture but show a modest reduction in PN soma area as a first sign of cerebellar disruption. Our results contrast the sensitivity of the developing cerebellum and remarkable resilience of the adult cerebellum to mutant ATXN1 and imply that SCA1 in this mouse model is both a developmental and neurodegenerative disorder.

Highlights

Spinocerebellar ataxia type 1 (SCA1) is a degenerative and progressive autosomal dominant disorder caused by expansion of a CAG repeat in the gene for the transcriptional regulator Ataxin-1 (ATXN1; Orr et al, 1993)
We found that exposure to mutant ATXN1 in young, developing mice caused ataxia and disrupted climbing fiber (CF), but not molecular layer (ML), architecture from as early as 4 weeks of age; in contrast mice exposed to ATXN1 from 6 weeks of age when cerebellar development was over, exhibited normal behavior and cerebellar architecture remained largely intact for up to 6 months
SCA1 mice that were exposed to mutant ATXN1 only after 6 weeks (using dox-induced repression of 82Q in this mouse (Zu et al, 2004)) motor behavior was largely intact even after 18 weeks of exposure to mutant ATXN1 in 6 month old mice (Figures 1D–F), 6 OFF 18 ON

Summary

Introduction

Spinocerebellar ataxia type 1 (SCA1) is a degenerative and progressive autosomal dominant disorder caused by expansion of a CAG repeat in the gene for the transcriptional regulator Ataxin-1 (ATXN1; Orr et al, 1993). ATXN1 normally interacts with a number of transcriptional regulators via its AXH domain and both gain and partial loss (Lim et al, 2008) of this function leads to a multitude of gene network expression changes in SCA1 (Ingram et al, 2016). The interaction between ATXN1 and the transcriptional repressor Capicua (Lam et al, 2006) and loss of the developmental transcription factor RORalpha (Serra et al, 2006) both directly contribute to cerebellar pathology and the progression of SCA1.

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Results

Conclusion