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

Abstract

BackgroundSpinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by a polyglutamine expansion in the ataxin‐1 protein resulting in neuropathology including mutant ataxin‐1 protein aggregation, aberrant neurodevelopment, and mitochondrial dysfunction.ObjectivesIdentify SCA1‐relevant phenotypes in patient‐specific fibroblasts and SCA1 induced pluripotent stem cells (iPSCs) neuronal cultures.MethodsSCA1 iPSCs were generated and differentiated into neuronal cultures. Protein aggregation and neuronal morphology were evaluated using fluorescent microscopy. Mitochondrial respiration was measured using the Seahorse Analyzer. The multi‐electrode array (MEA) was used to identify network activity. Finally, gene expression changes were studied using RNA‐seq to identify disease‐specific mechanisms.ResultsBioenergetics deficits in patient‐derived fibroblasts and SCA1 neuronal cultures showed altered oxygen consumption rate, suggesting involvement of mitochondrial dysfunction in SCA1. In SCA1 hiPSC‐derived neuronal cells, nuclear and cytoplasmic aggregates were identified similar in localization as aggregates in SCA1 postmortem brain tissue. SCA1 hiPSC‐derived neuronal cells showed reduced dendrite length and number of branching points while MEA recordings identified delayed development in network activity in SCA1 hiPSC‐derived neuronal cells. Transcriptome analysis identified 1050 differentially expressed genes in SCA1 hiPSC‐derived neuronal cells associated with synapse organization and neuron projection guidance, where a subgroup of 151 genes was highly associated with SCA1 phenotypes and linked to SCA1 relevant signaling pathways.ConclusionsPatient‐derived cells recapitulate key pathological features of SCA1 pathogenesis providing a valuable tool for the identification of novel disease‐specific processes. This model can be used for high throughput screenings to identify compounds, which may prevent or rescue neurodegeneration in this devastating disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Mutant androgen receptor induces neurite loss and senescence independently of ARE binding in a neuronal model of SBMA

“…Future studies will address this question and investigate the use of senolytics ( 67 ) as a therapeutic strategy for SBMA. Finally, neurite defects have recently been observed in other polyQ diseases ( 68 , 69 ). The relationship we identified between inclusion formation and neurite retraction suggests that mechanisms revealed herein may apply to other polyQ diseases, presenting an avenue for treatment that is independent of the disease-causing gene.…”

Hereditary Ataxias: From Bench to Clinic, Where Do We Stand?

“…Being able to develop humanized rodent models or human-based models, such as iPSC, is the current challenge. While the generation of induced cortical neuron and organoids has been achieved without major challenges [11,[263][264][265][266][267], the generation of PN and cerebellar organoids needs further optimization as the protocols available present low purity and maturity, and the survival of PN in cultures is still challenging [268][269][270][271]. These represent powerful tools for drug testing and the study of the pathophysiological mechanisms underlying HAs, allowing researchers to investigate pathogenic variants while maintaining the genetic background of patients.…”

Hereditary Ataxias: From Bench to Clinic, where Do We Stand?

“…Being able to develop humanized rodent models, or human-based models, such as iPSC, is the current challenge. While generation of induced cortical neuron and organoids have been achieved without major challenges [11,[257][258][259][260][261], the generation of PN and cerebellar organoids needs further optimization as protocols available present low purity and maturity, and survival of PN in culture is still challenging [262][263][264][265]. These represent powerful tools for drug testing and the study of pathophysiological mechanisms underlying HA, allowing to investigate pathogenic variants while maintaining the genetic background of the patients.…”