Abstract
Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by abnormal expansion of glutamine (Q) encoding CAG repeats in the gene Ataxin-1 (ATXN1). Although motor and balance deficits are the core symptoms of SCA1, cognitive decline is also commonly observed in patients. While mutant ATXN1 is expressed throughout the brain, pathological findings reveal severe atrophy of cerebellar cortex in SCA1 patients. The cerebellum has recently been implicated in diverse cognitive functions, yet to what extent cerebellar neurodegeneration contributes to cognitive alterations in SCA1 remains poorly understood. Much of our understanding of the mechanisms underlying pathogenesis of motor symptoms in SCA1 comes from mouse models. Reasoning that mouse models could similarly offer important insights into the mechanisms of cognitive alterations in SCA1, we tested cognition in several mouse lines using Barnes maze and fear conditioning. We confirmed cognitive deficits in Atxn1154Q/2Q knock-in mice with brain-wide expression of mutant ATXN1 and in ATXN1 null mice. We found that shorter polyQ length and haploinsufficiency of ATXN1 do not cause significant cognitive deficits. Finally, ATXN1[82Q] transgenic mice - with cerebellum limited expression of mutant ATXN1 - demonstrated milder impairment in most aspects of cognition compared to Atxn1154Q/2Q mice, supporting the concept that cognitive deficits in SCA1 arise from a combination of cerebellar and extra-cerebellar dysfunctions.
Original language | English (US) |
---|---|
Pages (from-to) | 117-131 |
Number of pages | 15 |
Journal | Human molecular genetics |
Volume | 29 |
Issue number | 1 |
DOIs | |
State | Published - Jan 1 2020 |
Bibliographical note
Funding Information:We thank Professor Pamela Stanley at the Albert Einstein College of Medicine for providing Lec3.2.8.1 cells; Miss Chi-Chun Huang at the Institute of Biomedical Sciences (IBMS),Academia Sinica (AS), for preparation of recombinant human galectin-3; Professor Kuo-I Lin at the Genomics Research Center, AS, and Dr. Hsien-Ya Lin at the Institute of Biological Chemistry, AS, for providing recombinant human galectin-8; and Mr. Ting-Jui Tu at the IBMS, AS, for designing and cloning the galectin-Flag-APEX2 constructs. We thank Dr. Chia-Lin Ho at Molecular Devices and the common equipment core facility of IBMS (Core Facility Project AS-CFII-108-113 and AS-CFII-108-115) and the Institute of Molecular Biology, AS, for assisting in DNA sequencing, image acquisition and flow cytometry analysis; the EM core facility of IBMS and ICOB, AS, for assisting in sample preparation and EM graph acquisition (Core Facility Project AS-CFII-108-119); the National RNAi Core Facility, AS, for providing shRNA reagents and plasmids. We thank Professor Chi-Yu Fu and Mr. Ferdie Fatiga at the Institute of Cellular and Organismic Biology (ICOB), AS, for their advice on APEX2-3,3-diaminobenzidine staining for electron microscopy (EM), and Dr. Jane M. Liu at Pomona College for reading and commenting on the manuscript. This work was supported by grants from Ministry of Science and Technology (MOST 104-0210-01-09-02, MOST 105-0210-01-13- 01 and MOST 106-0210-01-15-02), and Academia Sinica Thematic Project (AS-105-TP-B08).
Funding Information:
This work was supported by the Marija Cvetanovic’s start-up funds and funding from the Bob Allison Ataxia Research Center.
Publisher Copyright:
© 2019 The Author(s). Published by Oxford University Press. All rights reserved.