Objective: To study the effect of the PPP2R2B mutation on human induced pluripotent stem cell (iPSC) derived neurons in SCA12 patients.

Background: SCA12 is an autosomal dominant ataxia syndrome attributed to an increased number of CAG repeats due to a mutated PPP2R2B gene (encodes for PP2A). PP2A is known to regulate cellular processes by dephosphorylation, thereby controlling signal transduction pathways involved in cell growth, division, and survival.  SCA12 is characterized by late-onset ataxia and action tremor along with other cerebellar motor symptoms. Cognitive impairment is also a part of the disease spectrum, though masked due to profound motor manifestations. Radiological and post-mortem studies have revealed atrophy of both cerebellum and cortex, including the association areas. However, how this mutation impacts specific cell types, leading to such cognitive dysfunctions, is unclear. Since, brain biopsy is not feasible in such patients, iPSCs serve as an invaluable system for studying such disorders and potential therapeutic interventions.

Method: A genetically confirmed SCA12 patient and healthy sibling with similar demographics were identified at the movement disorder clinic, I-NK, Kolkata. After ethical approval and informed consent, iPSCs were derived, and further subjected to ectodermal lineage specification, followed by differentiation and maturation into neurons. To carry out detailed morphological analysis of the SCA12 neurons, cells were immunophenotyped for cytoskeletal proteins – MAP2ab in neurons and GFAP in astrocytes.

Results: Further, images captured were used for analysis of cell number, soma size and neuron-glia (N-G) ratio. Data suggests a significantly smaller soma size of the SCA12 neurons. Based on these results we further propose to study PP2A’s role in cytoskeletal modifications. The number of SCA12 neurons seemed to be higher, but N-G ratio was not different.

Conclusion: Other neurological disorders like Schizophrenia have reported similar decreases in cell sizes. The extent of a neuron’s axonal and dendritic arbor is correlated to size. A decrease in the same may reflect reduction in the afferent -efferent connectivity of neurons. This can subsequently be responsible for the cognitive deficits observed. The decreased soma size and the apparent differences in the number of neurons are currently being investigated in more detail in our laboratory.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/how-does-the-ppp2r2b-mutation-alter-neuronal-cytoskeletal-structure-in-sca12/