Developing neuroprotective strategies for proteinopathy. The lesions seen in the degenerating neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U) consist primarily of abnormal TDP-43 protein. Pathological TDP-43 containing deposits associated with motor neuron neurodegeneration are the hallmark pathology in over 90% of ALS cases, including both familial and sporadic types. How aggregated, ubiquitinated and phosphorylated TDP-43 protein causes neuronal dysfunction and neurodegeneration remains incompletely understood. This work focuses on extending previous studies to complete the molecular dissection of the mechanisms causing neurodegeneration in ALS and FTLD. In the previous funding period we characterized a C. elegans model of ALS mutation driven TDP-43 proteinopathy and investigated the molecular, cellular, and genomic basis of TDP-43 neurotoxicity. We identified phosphorylation of TDP-43 at serines 409/410 as a critical molecular species driving neurotoxicity, and identified kinases modulating neurodegeneration by controlling the accumulation of phosphorylated TDP-43.
The specific aims of this competitive renewal are: 1) Determine the relative toxicity of phosphorylated wild type TDP-43 and the role of kinase activation in the genesis of phosphorylated TDP-43; 2) Identify the cellular machinery responsible for detoxifying phosphorylated TDP-43 3) Dissect the mechanisms by which Ubiquilin mediates TDP-43 neuropathology and neurodegeneration. The development of neuroprotective strategies for TDP-43 related neuropathology in ALS and FTLD is the long term objective of this work. By completing the proposed experiments we will construct additional models of sporadic ALS/FTLD, address the critical question of whether or not pS409/410 TDP-43 is a neurotoxic species in mammals, dissect the molecular mechanism mediating TDP-43 toxicity and capitalize on this information to develop new translationally relevant neuroprotective strategies for targeting TDP-43 neurotoxicity.

Public Health Relevance

Pathological TDP-43 in either cortical or motor neurons causes neurodegenerative changes in a group of disorders known as TDP-43 proteinopathies which include frontotemporal lobar degeneration and amyotrophic lateral sclerosis. The progressive dementia and/or motor dysfunction caused by TDP-43 proteinopathy disorders have no effective treatment, cause severe disability, and lead to premature death. By identifying new neuroprotective strategies targeting phosphorylatedTDP-43 we hope to advance the development of therapeutic options for both FTLD and ALS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064131-07
Application #
8858691
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sutherland, Margaret L
Project Start
2008-12-01
Project End
2019-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
7
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Seattle Institute for Biomedical/Clinical Research
Department
Type
DUNS #
928470061
City
Seattle
State
WA
Country
United States
Zip Code
98108
Taylor, Laura M; McMillan, Pamela J; Liachko, Nicole F et al. (2018) Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration. Mol Neurodegener 13:7
Weeks, Janis C; Roberts, William M; Leasure, Caitlyn et al. (2018) Sertraline, Paroxetine, and Chlorpromazine Are Rapidly Acting Anthelmintic Drugs Capable of Clinical Repurposing. Sci Rep 8:975
Liachko, Nicole F; Saxton, Aleen D; McMillan, Pamela J et al. (2016) The phosphatase calcineurin regulates pathological TDP-43 phosphorylation. Acta Neuropathol 132:545-61
Guerrero, Erika N; Wang, Haibo; Mitra, Joy et al. (2016) TDP-43/FUS in motor neuron disease: Complexity and challenges. Prog Neurobiol 145-146:78-97
Salado, Irene G; Redondo, Miriam; Bello, Murilo L et al. (2014) Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis. J Med Chem 57:2755-72
Boyd, Justin D; Lee, Peter; Feiler, Marisa S et al. (2014) A high-content screen identifies novel compounds that inhibit stress-induced TDP-43 cellular aggregation and associated cytotoxicity. J Biomol Screen 19:44-56
Liachko, Nicole F; McMillan, Pamela J; Strovas, Timothy J et al. (2014) The tau tubulin kinases TTBK1/2 promote accumulation of pathological TDP-43. PLoS Genet 10:e1004803
Dohi, Kenji; Kraemer, Brian C; Erickson, Michelle A et al. (2014) Molecular hydrogen in drinking water protects against neurodegenerative changes induced by traumatic brain injury. PLoS One 9:e108034
McCormick, Allyson V; Wheeler, Jeanna M; Guthrie, Chris R et al. (2013) Dopamine D2 receptor antagonism suppresses tau aggregation and neurotoxicity. Biol Psychiatry 73:464-71
Liachko, Nicole F; McMillan, Pamela J; Guthrie, Chris R et al. (2013) CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration. Ann Neurol 74:39-52

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