Region-specific preservation of Purkinje cell morphology and motor behavior in the ATXN1[82Q] mouse model of spinocerebellar ataxia 1

Joshua J. White, Laurens W.J. Bosman, Francois G.C. Blot, Catarina Osório, Bram W. Kuppens, Wilhelmina H.J.J. Krijnen, Charlotte Andriessen, Chris I. De Zeeuw*, Dick Jaarsma, Martijn Schonewille

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)


Purkinje cells are the primary processing units of the cerebellar cortex and display molecular heterogeneity that aligns with differences in physiological properties, projection patterns, and susceptibility to disease. In particular, multiple mouse models that feature Purkinje cell degeneration are characterized by incomplete and patterned Purkinje cell degeneration, suggestive of relative sparing of Purkinje cell subpopulations, such as those expressing Aldolase C/zebrinII (AldoC) or residing in the vestibulo-cerebellum. Here, we investigated a well-characterized Purkinje cell-specific mouse model for spinocerebellar ataxia type 1 (SCA1) that expresses human ATXN1 with a polyQ expansion (82Q). Our pathological analysis confirms previous findings that Purkinje cells of the vestibulo-cerebellum, i.e., the flocculonodular lobes, and crus I are relatively spared from key pathological hallmarks: somatodendritic atrophy, and the appearance of p62/SQSTM1-positive inclusions. However, immunohistological analysis of transgene expression revealed that spared Purkinje cells do not express mutant ATXN1 protein, indicating the sparing of Purkinje cells can be explained by an absence of transgene expression. Additionally, we found that Purkinje cells in other cerebellar lobules that typically express AldoC, not only display severe pathology but also show loss of AldoC expression. The relatively preserved flocculonodular lobes and crus I showed a substantial fraction of Purkinje cells that expressed the mutant protein and displayed pathology as well as loss of AldoC expression. Despite considerable pathology in these lobules, behavioral analyses demonstrated a relative sparing of related functions, suggestive of sufficient functional cerebellar reserve. Together, the data indicate that mutant ATXN1 affects both AldoC-positive and AldoC-negative Purkinje cells and disrupts normal parasagittal AldoC expression in Purkinje cells. Our results show that, in a mouse model otherwise characterized by widespread Purkinje cell degeneration, sparing of specific subpopulations is sufficient to maintain normal performance of specific behaviors within the context of the functional, modular map of the cerebellum.

Original languageEnglish
Article numbere12946
JournalBrain Pathology
Issue number5
Publication statusPublished - 1 Sept 2021

Bibliographical note

Funding Information:
Support was provided by NWO-VENI (JJW), Off-Road fellowship from ZonMW (CO), ERC-Stg #680235 (MS), ZonMW memorabel (733050810) (DJ), as well as ERC-Adv and ERC-PoC (CDZ), EU-LISTEN (CDZ), Medical NeuroDelta (CDZ), NWO-ALW (CDZ), Zon-Mw (CDZ), Albinism NIN-Friend Foundation (CDZ), and INTENSE NWO-LSH (CDZ). We thank Laura Post, Timothy Ton, and Sabine van den Bos for technical assistance. We thank the anonymous reviewer for their meaningful comments that shaped the final manuscript.

Publisher Copyright:
© 2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology


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