# PP2Acα regulates cerebellar development via phosphorylation-dependent neuronal programs

## TL;DR

This study shows that PP2Acα is essential for cerebellar development by regulating phosphorylation and neuronal processes, impacting motor and cognitive functions.

## Contribution

The study reveals PP2Acα's role in cerebellar development through phosphoproteomic and proteomic profiling.

## Key findings

- PP2Acα loss leads to impaired motor coordination and cognitive performance in mice.
- PP2Acα regulates granule neuron proliferation, migration, and Purkinje cell organization.
- Phosphoproteomics identifies PP2Acα's role in cell cycle, RNA splicing, and cytoskeletal remodeling.

## Abstract

Cerebellar development requires precise control of phosphorylation, yet the contribution of protein phosphatases remains poorly understood. Here, we investigated the function of protein phosphatase 2A catalytic subunit alpha (PP2Acα) in cerebellar granule neurons. Conditional deletion of Ppp2ca using Atoh1-Cre mice resulted in impaired motor coordination and cognitive performance, reflecting disrupted cerebellar development. Histological analyses revealed abnormal granule neuron proliferation, migration, and defective Purkinje cell organization during early postnatal stages. Phosphoproteomic and proteomic profiling of primary granule neurons identified the PP2Acα-dependent regulation of cell cycle, cytoskeletal remodeling, RNA splicing, metabolism, and translation. Complementary profiling of whole cerebellar tissues uncovered broader system-level alterations affecting neuronal morphogenesis, mRNA processing, synaptic signaling, and behavior. Collectively, these findings establish PP2Acα as a critical regulator of cerebellar development through coordinated control of phosphorylation and protein homeostasis across cellular and system levels, providing mechanistic insights into phosphatase-related neurodevelopmental disorders.

•PP2Acα loss in granule neurons impairs motor coordination and behavior•PP2Acα controls granule neuron proliferation, migration, and Purkinje cell organization•Phosphoproteomics shows PP2Acα regulates cell cycle, RNA splicing, and cytoskeleton•PP2Acα coordinates phosphorylation and proteostasis across cellular and system-levels

PP2Acα loss in granule neurons impairs motor coordination and behavior

PP2Acα controls granule neuron proliferation, migration, and Purkinje cell organization

Phosphoproteomics shows PP2Acα regulates cell cycle, RNA splicing, and cytoskeleton

PP2Acα coordinates phosphorylation and proteostasis across cellular and system-levels

Biochemistry; Neuroscience; Developmental biology