Objective: This study aims to establish patient-derived induced pluripotent stem cell (iPSC) models of Spinocerebellar Ataxia Type 12 (SCA12) and investigate mitochondrial transcriptional alterations across cellular stages from iPSCs to iPSC-derived neural progenitor cells(NPCs) and neurons, while assessing mitochondrial functional changes in the differentiated neurons.

Background: SCA12 is an inherited neurodegenerative disorder caused by a CAG repeat expansion in PPP2R2B gene, encoding the Bβ subunit of protein phosphatase 2A. We recently reported mitochondrial gene dysregulation in peripheral blood of SCA12 patients; further validation in SCA12 neurons is needed [1]. Patient-derived iPSCs provide a valuable platform to investigate disease-associated mechanisms in human neuronal models.

Method: PBMCs from 2 genetically confirmed SCA12 and 2 healthy controls were reprogrammed into iPSCs [table1]. iPSCs were differentiated into 2D neuronal cultures [figure1]. Expression of PPP2R2B and mitochondrial dynamics genes (DNM1L, FIS1, MFN2, OPA1) was quantified by qRT-PCR across cellular stages. In neurons, mitochondrial membrane potential (MMP) was measured by TMRM live-cell fluorometry. Mitochondrial morphology and oxidative stress were assessed by confocal imaging using MitoTracker Green FM and MitoSOX Red.

Results: Transcriptional analysis revealed altered expression of PPP2R2B and mitochondrial dynamics genes across NPCs, and neurons [figure2], suggesting a persistent disease-associated transcriptional signature. SCA12 neurons exhibited a 47.97% increase in MMP relative to controls. Confocal imaging indicated a subtle alteration in mitochondrial network morphology and elevated oxidative stress [figure3]. These trends were reproducible across biological replicates, though statistical significance was not reached, likely due to limited sample size.

Conclusion: Increased MMP observed in SCA12 neurons may reflect altered mitochondrial dynamics, shifting toward a fused network state, supported by elevated fusion regulators OPA1 and MFN2. Concurrently, an elevated MitoSOX signal suggests mitochondrial stress in the neurons. These findings implicate mitochondrial perturbations as a contributing feature of SCA12 pathogenesis, which may be influenced by CAG repeat length and individual-specific responses, and highlight mitochondrial homeostasis as a potential axis for mechanistic investigation and therapeutic targeting.

[table1]

[figure1]

[figure2]

[figure3]

References: Ansari S, Rungta J, Banerjee R, et al. Mitochondrial quality control gene expression in peripheral blood mononuclear cells of SCA12 patients. Parkinsonism Relat Disord. Published online February 12, 2026. doi:10.1016/j.parkreldis.2026.108228

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MDS Abstracts - https://www.mdsabstracts.org/abstract/investigating-mitochondrial-integrity-in-spinocerebellar-ataxia-type-12-via-patient-derived-ipsc-models/