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Consensus Paper: Strengths and Weaknesses of Animal Models of Spinocerebellar Ataxias and Their Clinical Implications

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Abstract

Spinocerebellar ataxias (SCAs) represent a large group of hereditary degenerative diseases of the nervous system, in particular the cerebellum, and other systems that manifest with a variety of progressive motor, cognitive, and behavioral deficits with the leading symptom of cerebellar ataxia. SCAs often lead to severe impairments of the patient’s functioning, quality of life, and life expectancy. For SCAs, there are no proven effective pharmacotherapies that improve the symptoms or substantially delay disease progress, i.e., disease-modifying therapies. To study SCA pathogenesis and potential therapies, animal models have been widely used and are an essential part of pre-clinical research. They mainly include mice, but also other vertebrates and invertebrates. Each animal model has its strengths and weaknesses arising from model animal species, type of genetic manipulation, and similarity to human diseases. The types of murine and non-murine models of SCAs, their contribution to the investigation of SCA pathogenesis, pathological phenotype, and therapeutic approaches including their advantages and disadvantages are reviewed in this paper. There is a consensus among the panel of experts that (1) animal models represent valuable tools to improve our understanding of SCAs and discover and assess novel therapies for this group of neurological disorders characterized by diverse mechanisms and differential degenerative progressions, (2) thorough phenotypic assessment of individual animal models is required for studies addressing therapeutic approaches, (3) comparative studies are needed to bring pre-clinical research closer to clinical trials, and (4) mouse models complement cellular and invertebrate models which remain limited in terms of clinical translation for complex neurological disorders such as SCAs.

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Abbreviations

AAV:

Adeno-associated virus

ADCA:

Autosomal dominant cerebellar ataxia

ALS:

Amyotrophic lateral sclerosis

ATXN:

Ataxin

BBB:

Blood-brain barrier

CIC:

Capicua

CMA:

Chaperone-mediated autophagy

CMV:

Cytomegalovirus

CN:

Cerebellar nuclei

CNS:

Central nervous system

CRISPR:

Clustered regularly interspaced short palindromic repeats

DNMT1:

DNA methyltransferase 1 mutation

Dox:

Doxycycline

DRPLA:

Dentatorubral-pallidoluysian atrophy

eIF2α:

Eukaryotic translation initiation factor 2 subunit 1

FGF:

Fibroblast growth factor

HSPs:

Hereditary spastic paraplegias

IRES:

Internal ribosomal entry site

KI:

Knock-in

LAMP2A:

Lysosome-associated protein 2A

LTD:

Long-term depression

LTP:

Long-term potentiation

miR-RORα:

MicroRNA against RORα

MSCV:

Murine stem cell virus

NfL:

Neurofilament light chain

NL/NP:

Neuronal loss/pathology

NLS:

Nuclear localization signal

PC:

Purkinje cell

RORα:

Retinoid-related orphan receptor α

ROS:

Reactive oxygen species

SAGA:

Spt-Ada-GCN5 acetyltransferase

SCA:

Spinocerebellar ataxia

SN:

Substantia nigra

STAU:

Staufen-1 protein

Tg:

Transgenic

TRE:

Tetracycline response element

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Funding

The work on this article was supported by the following grants and projects: Charles University Research Fund (project number Q39 and project no. CZ.02.1.01/0.0/0.0/16_019/0000787) “Fighting INfectious Diseases,” awarded by the Ministry of Education, Youth and Sports of the Czech Republic, financed from the European Regional Development Fund (Jan Cendelin, Filip Tichanek, and Jan Tuma); R01 NS197387, R01NS109077, National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) (Marija Cvetanovic); Brain/MINDS from Japan Agency for Medical Research and development, AMED (Grant Number JP20dm0207057), KAKENHI (Grant Number 18H02521) (Hirokazu Hirai); grants R37NS033123, R21NSNS103009, and UO1NS103883 from the National Institutes of Health (USA) (Stefan M. Pulst); (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) grants R21NS103009, R01NS097903, R37NS033123, and U01NS103883 (Mandi Gandelman)Gandelman); and National Institutes of Health/National Institute of Neurological Disorders and Stroke grants RO1-NS022920 and RO1-NS045667 (Harry T. Orr).

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Authors and Affiliations

  1. Department of Pathophysiology, Faculty of Medicine in Pilsen, Charles University, alej Svobody 75, 323 00, Plzen, Czech Republic

    Jan Cendelin, Filip Tichanek & Jan Tuma

  2. Laboratory of Neurodegenerative Disorders, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, alej Svobody 75, 323 00, Plzen, Czech Republic

    Jan Cendelin & Filip Tichanek

  3. Department of Neuroscience, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA

    Marija Cvetanovic

  4. Department of Neurology, University of Utah, 175 North Medical Drive East, Salt Lake City, UT, 84132, USA

    Mandi Gandelman & Stefan M. Pulst

  5. Department of Neurophysiology and Neural Repair, Gunma University Graduate School of Medicine, 3-39-22, Gunma, 371-8511, Japan

    Hirokazu Hirai

  6. Viral Vector Core, Gunma University Initiative for Advanced Research (GIAR), Gunma, 371-8511, Japan

    Hirokazu Hirai

  7. Department of Laboratory Medicine and Pathology, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA

    Harry T. Orr

  8. Department of Neurology and German Center for Vertigo and Balance Disorders, Hospital of the Ludwig-Maximilians University, Munich, Campus Grosshadern, Marchioninistr. 15, 81377, Munich, Germany

    Michael Strupp

  9. The Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7843, San Antonio, TX, 78229, USA

    Jan Tuma

  10. Unité des Ataxies Cérébelleuses, Service de Neurologie, CHU-Charleroi, Charleroi, Belgium

    Mario Manto

  11. Service des Neurosciences, Université de Mons, UMons, Mons, Belgium

    Mario Manto

Authors
  1. Jan Cendelin
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  2. Marija Cvetanovic
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  3. Mandi Gandelman
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  4. Hirokazu Hirai
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  5. Harry T. Orr
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  6. Stefan M. Pulst
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  7. Michael Strupp
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  8. Filip Tichanek
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  9. Jan Tuma
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  10. Mario Manto
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Contributions

The authors were responsible for drafting specific sections, and all of them revised and contributed to the entire article.

Corresponding author

Correspondence to Jan Cendelin.

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Conflict of Interest

M. Strupp is Joint Chief Editor of the Journal of Neurology, Editor in Chief of Frontiers of Neuro-otology, and Section Editor of F1000. He has received speaker’s honoraria from Abbott, Actelion, Auris Medical, Biogen, Eisai, Grünenthal, GSK, Henning Pharma, Interacoustics, MSD, Otometrics, Pierre-Fabre, TEVA, UCB, and Viatris. He is a shareholder and investor of IntraBio. He is the distributor of “M-glasses” and the “Positional vertigo” App. He acts as a consultant for Abbott, Actelion, Auris Medical, Heel, IntraBio, and Sensorion. M. Manto is Editor-in-Chief of The Cerebellum and Cerebellum and Ataxias. He has received royalties from Springer, Cambridge University Press, and Elsevier.

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Cendelin, J., Cvetanovic, M., Gandelman, M. et al. Consensus Paper: Strengths and Weaknesses of Animal Models of Spinocerebellar Ataxias and Their Clinical Implications. Cerebellum 21, 452–481 (2022). https://doi.org/10.1007/s12311-021-01311-1

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