Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle atrophy and spasticity due to degeneration of upper and lower motor neurons. Patients typically succumb to respiratory failure within 3-5 years of onset, with no effective therapies presently available. An important breakthrough in the understanding of ALS was recently provided by the (i) identification of pathologic aggregates of a protein called TDP43 in motor neurons from ALS patients, and (ii) the identification of dominantly inherited mutations in TDP43 in patients with familial ALS, solidifying the importance of TDP43 in the pathogenesis of ALS. TDP43 is a ubiquitiously expressed DNA/RNA binding protein capable of regulating transcription and alternative splicing, though its normal physiologic functions and role in ALS pathogenesis remain poorly understood. In our preliminary studies we have generated and characterized a mouse model which expresses a disease associated TDP43 mutant under the control of the mouse Prion promoter (Prp-TDP43A315T), and found that these mice develop a progressive and fatal neurodegenerative disease remarkably similar to ALS, recapitulating key aspects of the pathology including selective vulnerability of cortical layer 5 and spinal motor neurons. Based on these findings we propose that the molecular and cellular basis of selective vulnerability of cortical and spinal motor neurons in ALS are shared between mice and humans, and that misregulation of mRNA transcription or splicing by mutant TDP43 is a fundamental mechanism of disease in TDP43-related neurodegeneration. This proposal outlines experiments to refine our understanding of TDP43-related neurodegeneration. We propose to (1) characterize the phenotype of newly generated mouse lines expressing wild-type and disease mutant forms of TDP43;(2) define the relative contributions of neuronal and glial cells to neurodegeneration due to TDP43 mutations;and (3) identify transcriptional alterations and DNA/RNA targets of TDP43 in neurons selectively vulnerable to TDP43-induced neurodegeneration using a functional genomics approach. These studies will examine previously unexplored pathways of ALS pathogenesis, and identify new avenues for therapeutics development.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is a uniformly fatal neurodegenerative disease, for which no effective treatments are available. We have developed a new mouse model of this disease, and are using it to better understand what causes nerve cells to degenerate in ALS, in order to design and test new treatments for the disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Sutherland, Margaret L
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Cedars-Sinai Medical Center
Los Angeles
United States
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Lall, Deepti; Baloh, Robert H (2017) Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia. J Clin Invest 127:3250-3258
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