Research Grant Award

Elizabeth O'Hearn, MD

Johns Hopkins School of Medicine
Spinocerebellar ataxia type 12 (SCA 12): Investigate PP2A regulation of Group I metabotropic receptors

Spinocerebellar ataxia type 12 (SCA12) is an autosomal dominant (AD) neurologic disorder in which tremor and ataxia are prominent signs. SCA12 has been linked to a trinucleotide CAG repeat expansion mutation in the gene PPP2R2B. This gene encodes a regulatory subunit of the enzyme protein phosphatase 2A (PP2A). PP2A controls the phosphorylation status and, therefore, the activity of many different proteins in the cell. The mechanisms by which the mutation in PPP2R2B results in neuronal dysfunction and degeneration in SCA12 are not known.

The goal of this grant is to explore whether the mutation in PPP2R2B results in altered phosphorylation and consequently in dysregulation of the activity of Group I metabotropic receptors (mGluR1 and mGluR5). Group I metabotropic glutamate receptors trigger the release of calcium from intracellular stores and are widely distributed in the brain. These receptors are involved in many brain functions including synaptic plasticity that underlies learning and memory. mGluR1 and mGluR5 are essential for motor control by the cerebellum which is required for normal walking and limb coordination. Abnormal function in this class of glutamate receptors has been linked to cerebellar dysfunction and ataxia.

The aim of this research is to study whether the activity of Group I metabotropic glutamate receptors is regulated by the enzyme PP2A when it contains the B regulatory subunit encoded by the gene mutated in SCA12. Abnormal function of these glutamate receptors may contribute to ataxia and cognitive abnormalities in patients with SCA12. Studies of the mechanisms by which these receptors are regulated by phosphorylation may lead to new pharmacologic therapy for ataxia in SCA12 and other cerebellar disorders.