Human Induced Pluripotent Stem Cell-Based Modelling of Spinocerebellar Ataxias

Abstract

Dominant spinocerebellar ataxias (SCAs) constitute a large group of phenotypically and genetically heterogeneous disorders that mainly present with dysfunction of the cerebellum as their main hallmark. Although animal and cell models have been highly instrumental for our current insight into the underlying disease mechanisms of these neurodegenerative disorders, they do not offer the full human genetic and physiological context. The advent of human induced pluripotent stem cells (hiPSCs) and protocols to differentiate these into essentially every cell type allows us to closely model SCAs in a human context. In this review, we systematically summarize recent findings from studies using hiPSC-based modelling of SCAs, and discuss what knowledge has been gained from these studies. We conclude that hiPSC-based models are a powerful tool for modelling SCAs as they contributed to new mechanistic insights and have the potential to serve the development of genetic therapies. However, the use of standardized methods and multiple clones of isogenic lines are essential to increase validity and reproducibility of the insights gained. Graphical Abstract

Patient-Specific iPSCs-Based Models of Neurodegenerative Diseases: Focus on Aberrant Calcium Signaling

“…Currently, the presented iPSCs-based SCA models are ( Table 4 ): SCA 1 [ 174 , 175 ], SCA 2 [ 176 , 177 , 178 ], SCA 3 [ 58 , 59 , 60 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 ], SCA 6 [ 42 , 189 ], SCA 7 [ 190 , 191 , 192 ], SCA 14 [ 193 ], SCA 16 [ 194 ], SCA 36 [ 195 ], and SCA 42 [ 167 ]. More data accumulated on iPSCs-based models of different SCAs can be found in the review by Hommersom et al, 2021 [ 196 ].…”

Advances in Modeling Polyglutamine Diseases Using Genome Editing Tools

“…Cellular models that connect the advantages of ESCs and patient-derived fibroblasts are iPSCs. iPSCs contain patient-specific genetic information, divide unlimitedly and can be differentiated into any disease-relevant cell populations, including neurons [152,153]. In their undifferentiated form, iPSCs can be a good model for studying molecular changes typical of the early phenotypes of polyQ diseases, such as gene expression, cellular signaling and formation of aggregates [153].…”

Spinocerebellar Ataxia Type 1 Characteristics in Patient‐Derived Fibroblast and iPSC‐Derived Neuronal Cultures

“…SCA1 mouse models demonstrate alterations in mitochondrial proteins, impairment of the electron transport chain (ETC) complexes, decrease in adenosine triphosphate (ATP) activity, and deficits in mitochondrial oxidative phosphorylation 23‐25 . These are important disease‐modifying processes as both motor behavior deficits and disease pathology can be ameliorated in SCA1 mouse models by the mitochondria‐targeting antioxidant MitoQ or the ETC complex II electron donor, succinic acid 25,27 …”

“…Human induced pluripotent stem cells (hiPSCs) derived from patients can be used for in vitro disease modeling 26 . These cell models have been used to study pathogenic processes, including protein aggregation, Purkinje cell (PC) development, and altered composition of glutamatergic receptors and test intervention strategies for polyQ diseases 20,27‐31 . We previously generated and characterized three hiPSC clones of a SCA1 patient, but so far, SCA1 hiPSC‐based disease modeling has not been described 32 …”

“…[23][24][25] These are important disease-modifying processes as both motor behavior deficits and disease pathology can be ameliorated in SCA1 mouse models by the mitochondria-targeting antioxidant MitoQ or the ETC complex II electron donor, succinic acid. 25,27 Despite advances in SCA1 research, there is no cure for SCA1. 9 For the development of novel treatments, there is a need to establish patient-derived disease models that mimic main aspects of the disease.…”