A point mutation in TRPC3 causes abnormal Purkinje cell development and cerebellar ataxia in moonwalker mice

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.cerebellum ͉ dendritogenesis ͉ trp channel ͉ mouse mutant T he inherited cerebellar ataxias are a complex group of neurodegenerative disorders characterized by loss of balance and coordination (1-3). Cerebellar ataxia is caused by the degeneration of Purkinje cells, which form the sole output of the cerebellum. To date, more than 50 different inherited forms of cerebellar ataxia are known (4). Importantly, increasing evidence points to the existence of common pathological pathways in different forms of ataxia, including transcriptional regulation, protein aggregation, and calcium homeostasis, which trigger the degeneration of Purkinje cells in these disorders (1, 5). However, the molecular mechanisms mediating these pathways remain poorly understood.To identify gene products that might be key to cerebellar degeneration, we used a phenotype-driven approach to screen for ataxic behavior in a large cohort of N-ethyl-N-nitrosourea (ENU)-mutagenized mice (6). Here, we report that a point mutation (T635A) in the C3-type transient receptor potential (TRPC3) channel in the mouse results in Purkinje cell degeneration and cerebellar ataxia. We also find that the development of dendrites is severely impaired in mutant Purkinje cells. Notably, the identified dominant gain-of-function mutation in TRPC3 provides insight into the function of TRPC3 that powerfully complements the findings obtained from the recently published TRPC3 knockout mouse (7). Our findings suggest that TRPC3 is a regulator of development and survival of Purkinje cells, and link aberrant TRPC3 function to cerebellar disease.

Loss of the Neuron-Specific F-Box Protein FBXO41 Models an Ataxia-Like Phenotype in Mice with Neuronal Migration Defects and Degeneration in the Cerebellum

“…Because ϳ40% of ataxias are of unknown genetic causes (Sailer and Houlden, 2012), the search for causative genes is imperative and the discovery of new genes such as the FBXO41 gene and the recently identified TRCP3 gene as critical factors of cerebellar development and integrity are important because mutations and deletions in the these genes might be associated with unresolved forms of congenital ataxias (Becker et al, 2009;Becker, 2015). In addition, future elucidation of the FBXO41 pathway will shed more light onto the mechanisms that regulate cerebellar development and will contribute to our understanding of the role of FBXO41 in proper motor coordination and possibly disease.…”

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

“…Purkinje neurons in the SCAs undergo dramatic simplification of their otherwise complex dendritic arbor. Interestingly, several mouse models with mutations in the calcium channel genes Trpc3 and Grid2 (in moonwalker and lurcher mice, respectively) result in increased dendritic calcium load and are associated with similar Purkinje neuron dendritic atrophy [102,103].…”

Light-dependent Phosphorylation of the Drosophila Transient Receptor Potential Ion Channel

“…In contrast, Src kinase activity is required for the activation of TRPC3 by diacylglycerol (9), and Fyn kinase phosphorylates and thereby increases the activity of TRPC6 (10). Abolition of the putative protein kinase C phosphorylation site Thr 635 in the S4/S5 linker region of TRPC3 by mutation results in increased channel activity and was found to underlie the phenotype of moonwalker mice, which is caused by loss of Purkinje cells (11). The regulation of the capsaicin-and heat-sensitive TRPV1 channel through phosphorylation of serine residues by protein kinase C is also well established (12)(13)(14).…”