Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord. Frontotemporal dementia (FTD) is early-onset dementia caused by degeneration of the frontal and temporal lobes with cognitive deficits and behavioral and language abnormalities. FTD shares pathophysiological features with ALS. A hexanucleotide repeat expansion in an intron of C9orf72 is the most frequently reported genetic cause of both diseases. Most of the pathophysiological studies of C9orf72 ALS/FTD and other types of ALS so far have been focused on upper and lower motor neurons. Recently, several functional studies have detected lower gray matter volume in the cerebellum in pre-symptomatic C9orf72 repeat expansion carriers, and anatomical evidence in C9orf72 disease mouse models have demonstrated cerebellar degeneration. Furthermore, pathology reports using postmortem or patient cells have demonstrated inclusions, RNA foci, dipeptide repeat proteins, and decreased C9orf72 mRNA and protein levels in the cerebellum, especially Purkinje cells, implicating cerebellar dysfunction in the pathogenesis of C9orf72 ALS/FTD. However, there are very few studies in animal disease models focusing on the cerebellum. Our strong preliminary data on C9orf72 knockout mice has revealed motor deficits and altered Purkinje cell activity. The functional significance of the cerebellum in the C9orf72 ALS/FTD pathogenesis is not known, let alone the detailed mechanisms. These unknowns hamper efforts to understand the pathophysiology of C9orf72 ALS/FTD and to develop effective therapies for patients. The overall goal of our research is to use transgenic mice to study the pathophysiology of C9orf72 ALS/FTD. The specific goal of this application is to characterize mouse models of C9orf72 ALS/FTD to determine the role of cerebellum in the pathogenesis of ALS and FTD. We hypothesize that at the presymptomatic stage, the C9orf72 mutant mice have motor deficits in coordination and balance, anatomical and functional deficits in the cerebellum, especially in the Purkinje cells due to the loss of function of C9orf72 protein and changes in the ion channels. We plan to test our hypothesis with the following Specific Aims: (1) we will examine C9orf72 mutant mice in the behavioral test battery, (2) we will characterize neuronal morphology, passive membrane properties, and intrinsic excitabilities of Purkinje cells, and (3) we will perform acutely dissociated Purkinje cell recording and Western blot analysis to determine ion channels involved in the altered firing of Purkinje cells. The successful completion of the Aims will expand the current knowledge concerning the involvement of the cerebellum in C9orf72-mediated ALS/FTD. This should significantly increase our understanding of the pathophysiology of C9orf72 ALS/FTD and contribute to the pathophysiological studies of other genetic ALS. Furthermore, the outcome of the research will support cerebellum as a potential therapeutic target to treat C9orf72 ALS/FTD. .

Public Health Relevance

Close to 16,000 individuals have ALS, and up to 50,000 persons are affected with behavioral variant FTD in the US. These represent a significant economic burden on both patients and their caregivers. We will use biochemistry, electrophysiology, and behavior analysis to determine how cerebellum, particularly Purkinje cells, contribute to ALS and FTD related symptoms.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Gubitz, Amelie
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University of Florida
United States
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