Spinocerebellar ataxias (SCAs) are neurodegenerative syndromes of autosomal inheritance. They are characterized by cerebellar dysfunction and may be associated with other neurological signs such as dystonia and myoclonus. No cure is currently available for these syndromes, largely because we lack a detailed understanding of the cellular mechanisms causing the disease. The Moonwalker (MWK) mouse is a rodent model of the human spinocerebellar ataxia 41 (SCA41). It carries a gain of function mutation of the TRPC3 channel. Cerebellar expression of TRPC3 is highly cell-specific, being present only in Purkinje cells (PCs) and unipolar brush cells (UBCs). In the early stages of the MWK ataxia PCs are functionally impaired and UBCs are almost completely ablated. Thus, a critical question raised by the MWK ataxia model is whether either the PC impairment or the UBC loss can autonomously cause the disease, or whether a combination of the two is required to cause the ataxic phenotype. To answer this question it is necessary to selectively express the MWK mutation in one and not the other cell type. In order to do so, we propose to make a new Cre-dependent TRPC3mwk knock-in mouse line (TRPC3mwk fx) by using a genetic switch (FLEx) strategy. We will breed these mice with PC-specific Pcp2 Cre mice to selectively drive expression TRPC3mwk in PCs and we will characterize the motor phenotype and the cerebellar pathology in the PC-specific TRPC3mwk mice Successful completion of these experiments will shed light on the pathogenic mechanism of the MWK ataxia and will allow dissecting the selective contribution of PC impairment. This new transgenic (TRPC3mwk fx) mouse will also be essential for future experiments that will take advantage of this mouse to selectively express the MWK mutation in UBCs, and investigate the role of these neurons in the MWK ataxia and, more in general, in the cerebellar network. Additionally, this mouse line may also help studying the role of TRPC3 in other cell populations where this channel is expressed, within and outside the CNS.
|Effective start/end date||2/1/20 → 1/31/22|
- National Institute of Neurological Disorders and Stroke (1R03NS114738-01)