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Neuropathol Appl Neurobiol. 2019 Jan 12. doi: 10.1111/nan.12540. [Epub ahead of print]

Short Review: Investigating ARSACS: models for understanding cerebellar degeneration.

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Stem Cells Therapies in Neurodegenerative Diseases Lab, Research Center "Principe Felipe", Valencia, Spain.
Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders and Service of Genomics and Translational Genetics, Research Center "Principe Felipe", Valencia, Spain.
Institute of Experimental Medicine, Department of Neuroscience, Academy of Science of the Czech Republic, Prague, Czech Republic.
National Stem Cell Bank-Valencia Node, Platform for Proteomics, Genotyping and Cell Lines, PRB3, ISCIII, Research Center "Principe Felipe", Valencia, Spain.


Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that includes progressive cerebellar dysfunction. ARSACS is caused by an autosomal recessive loss-of-function mutation in the SACS gene, which encodes for SACSIN. Although animal models are still necessary to investigate the role of SACSIN in the pathology of this disease, more reliable human cellular models need to be generated to better understand the cerebellar pathophysiology of ARSACS. The discovery of human induced pluripotent stem cells (hiPSC) has permitted the derivation of patient-specific cells. These cells have an unlimited self-renewing capacity and the ability to differentiate into different neural cell types, allowing studies of disease mechanism, drug discovery and cell replacement therapies. In this study, we discuss how the hiPSC-derived cerebellar organoid culture offers novel strategies for targeting the pathogenic mutations related to ARSACS. We also highlight the advantages and challenges of this 3D cellular model, as well as the questions that still remain unanswered.


ARSACS ; 3D organoids; ataxia; cerebellum; disease modelling; induced pluripotent stem cells


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