A Point Mutation in TRPC3 Causes Abnormal Purkinje Cell Development and Cerebellar Ataxia in Moonwalker Mice

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2009 Apr 9

PMID 19351902

Citations 117

Authors

Esther B E Becker

Peter L Oliver

Maike D Glitsch

Gareth T Banks

Francesca Achilli

Andrea Hardy

Patrick M Nolan

Elizabeth M C Fisher

Kay E Davies

Affiliations

Soon will be listed here.

Abstract

The hereditary ataxias are a complex group of neurological disorders characterized by the degeneration of the cerebellum and its associated connections. The molecular mechanisms that trigger the loss of Purkinje cells in this group of diseases remain incompletely understood. Here, we report a previously undescribed dominant mouse model of cerebellar ataxia, moonwalker (Mwk), that displays motor and coordination defects and loss of cerebellar Purkinje cells. Mwk mice harbor a gain-of-function mutation (T635A) in the Trpc3 gene encoding the nonselective transient receptor potential cation channel, type C3 (TRPC3), resulting in altered TRPC3 channel gating. TRPC3 is highly expressed in Purkinje cells during the phase of dendritogenesis. Interestingly, growth and differentiation of Purkinje cell dendritic arbors are profoundly impaired in Mwk mice. Our findings define a previously unknown role for TRPC3 in both dendritic development and survival of Purkinje cells, and provide a unique mechanism underlying cerebellar ataxia.

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