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The extra-cerebellar effects of spinocerebellar ataxia type 1 (SCA1): looking beyond the cerebellum

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Abstract

Spinocerebellar ataxia type 1 (SCA1) is one of nine polyglutamine (polyQ) diseases and is characterized as an adult late-onset, progressive, dominantly inherited genetic disease. SCA1 is caused by an increase in the number of CAG repeats in the ATXN1 gene leading to an expanded polyQ tract in the ATAXIN-1 protein. ATAXIN-1 is broadly expressed throughout the brain. However, until recently, SCA1 research has primarily centered on the cerebellum, given the characteristic cerebellar Purkinje cell loss observed in patients, as well as the progressive motor deficits, including gait and limb incoordination, that SCA1 patients present with. There are, however, also other symptoms such as respiratory problems, cognitive defects and memory impairment, anxiety, and depression observed in SCA1 patients and mouse models, which indicate that there are extra-cerebellar effects of SCA1 that cannot be explained solely through changes in the cerebellar region of the brain alone. The existing gap between human and mouse model studies of extra-cerebellar regions in SCA1 makes it difficult to answer many important questions in the field. This review will cover both the cerebellar and extra-cerebellar effects of SCA1 and highlight the need for further investigations into the impact of mutant ATXN1 expression in these regions. This review will also discuss implications of extra-cerebellar effects not only for SCA1 but other neurodegenerative diseases showing diverse pathology as well.

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Abbreviations

SCA1:

Spinocerebellar ataxia type 1

CAG:

Cytosine-adenine-guanine

polyQ:

Polyglutamine

SCAs:

Spinocerebellar ataxias

MRI:

Magnetic resonance imaging

CNS:

Central nervous system

CIC:

Capicua

RBMs:

RNA binding motif proteins

PC:

Purkinje cell

CCAS:

Cerebellar cognitive affective syndrome

WT:

Wild-type

Tg:

Transgenic

Pcp2:

Purkinje cell protein 2

KI:

Knock-in

PHQ:

Patient Health Questionnaire

KO:

Knock-out

ASO:

Antisense oligonucleotide

CMAP:

Compound motor action potential

SGL:

Subgranular layer

NIs:

Nuclear inclusions

CA1:

Cornu Ammonis 1

CA2:

Cornu Ammonis 1

GM:

Gray matter

WM:

White matter

SCA2:

Spinocerebellar ataxia type 2

SCA3:

Spinocerebellar ataxia type 3

HD:

Huntington’s disease

TFs:

Transcription factors

NLS:

Nuclear localization signal

SAR:

Self-association region

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Acknowledgements

We would like to thank all members of the Lim laboratory for providing valuable comments and feedback. The figures were created with BioRender.com.

Funding

This work was supported by National Institute of Health grants AG076154 (J.L.), AG074609 (J.L.), AG066447 (J.L.), NS083706 (J.L.), NS088321 (J.L.), MH119803 (J.L.), T32 NS007224 (K.L.), and the Lo Graduate Fellowship for Excellence in Stem Cell Research (K.L.).

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Authors and Affiliations

  1. Department of Genetics, Yale School of Medicine, 295 Congress Avenue, BCMM 154E, New Haven, CT, 06510, USA

    Victor Olmos, Neha Gogia & Janghoo Lim

  2. Interdepartmental Neuroscience Program, Yale School of Medicine, 295 Congress Avenue, BCMM 154E, New Haven, CT, 06510, USA

    Kimberly Luttik & Janghoo Lim

  3. Department of Neuroscience, Yale School of Medicine, 295 Congress Avenue, BCMM 154E, New Haven, CT, 06510, USA

    Kimberly Luttik & Janghoo Lim

  4. Yale College, New Haven, CT, 06510, USA

    Fatema Haidery

  5. Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale School of Medicine, 295 Congress Avenue, BCMM 154E, New Haven, CT, 06510, USA

    Janghoo Lim

  6. Yale Stem Cell Center, Yale School of Medicine, 295 Congress Avenue, BCMM 154E, New Haven, CT, 06510, USA

    Janghoo Lim

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VO and JL developed the concept. VO, NG, KL, FH, and JL wrote the manuscript. All authors reviewed and edited the manuscript and provided comments.

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Correspondence to Janghoo Lim.

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Olmos, V., Gogia, N., Luttik, K. et al. The extra-cerebellar effects of spinocerebellar ataxia type 1 (SCA1): looking beyond the cerebellum. Cell. Mol. Life Sci. 79, 404 (2022). https://doi.org/10.1007/s00018-022-04419-7

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