Induced Pluripotent Stem Cells in Huntington’s Disease: Disease Modeling and the Potential for Cell-Based Therapy

Abstract

Huntington’s disease (HD) is an incurable neurodegenerative disorder that is characterized by motor dysfunction, cognitive impairment, and behavioral abnormalities. It is an autosomal dominant disorder caused by a CAG repeat expansion in the huntingtin gene, resulting in progressive neuronal loss predominately in the striatum and cortex. Despite the discovery of the causative gene in 1993, the exact mechanisms underlying HD pathogenesis have yet to be elucidated. Treatments that slow or halt the disease process are currently unavailable. Recent advances in induced pluripotent stem cell (iPSC) technologies have transformed our ability to study disease in human neural cells. Here, we firstly review the progress made to model HD in vitro using patient-derived iPSCs, which reveal unique insights into illuminating molecular mechanisms and provide a novel human cell-based platform for drug discovery. We then highlight the promises and challenges for pluripotent stem cells that might be used as a therapeutic source for cell replacement therapy of the lost neurons in HD brains.

Pueraria lobata and Daidzein Reduce Cytotoxicity by Enhancing Ubiquitin-Proteasome System Function in SCA3-iPSC-Derived Neurons

“…The rapid development in the iPSC field and the potential of iPSC to differentiate into different cell types not only offer great opportunities to study the pathogenesis of neurodegenerative diseases including SCA3 but also provide a platform to identify new therapeutic strategies [28–31]. In the past decade, neuronal cells derived from patient-specific iPSCs have been generated to model neurodegenerative diseases such as PD [32, 33], Alzheimer's disease (AD) [34, 35], and HD [36, 37], and relatively handful iPSC studies focused on cerebellar ataxias including Friedreich's ataxia (FRDA) [38–43] and SCAs: SCA2 [44], SCA3 [45–48], SCA6 [49], SCA7 [50], SCA14 [51], and SCA36 [52]. Koch et al first reported that L-glutamate-induced excitation of SCA3-iPSC-derived neurons initiated calpain-dependent proteolysis of ATXN3 followed by the formation of SDS-insoluble aggregates [46].…”

Unveiling synapse pathology in spinal bulbar muscular atrophy by genome-wide transcriptome analysis of purified motor neurons derived from disease specific iPSCs

“…However, the consistency between the trinucleotide repeat instability in patients' tissues and those in iPSCs is still not clear in other triplet repeat diseases, such as Huntington disease (HD), caused by CAG repeat expansion in the Huntingtin (HTT) gene, and myotonic dystrophy (DM1), caused by CTG repeat expansion in the 3′ UTR of the DMPK gene, both of which exhibit somatic instability of the repeats, and significant anticipation [30]. Although the augmentation of the CAG repeat expansion was not observed during reprograming into iPSCs, the long-term maintenance of iPSCs, and the neural differentiation in HD disease-specific iPSCs [31,32], all 41 iPSC clones established from DM1 patients' fibroblasts showed different CTG repeat length as expected [33]. Thus, trinucleotide repeat instability during reprogramming does not completely correspond to that observed in patients' tissues, and the details remain yet to be elucidated.…”

Light-Activated Cell Identification and Sorting (LACIS): A New Method to Identify and Select Edited Clones on a Microfluidic Device

“…In addition, our flexible platform could enhance other gene-editing workflows. For instance, our pipeline could facilitate the study of genetic disorders through the generation of heterozygous or homozygous model cell lines (ESCs or iPSCs) bearing knock-in disease mutation (17)(18)(19).…”