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Investigating the Contribution of ALS/FTD-Associated Mutations in the NEK1 Kinase to Disease Pathophysiology

Award Number: R01NS134166
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Investigating the Contribution of ALS/FTD-Associated Mutations in the NEK1 Kinase to Disease Pathophysiology - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that is characterized by a progressive inability to control muscle movement. ALS patients are often comorbid with frontotemporal dementia (FTD), also known as ALS/FTD. The clinical manifestation of ALS is mediated by the selective dysfunction and degeneration of upper and lower motor neurons (MNs) that connect the CNS to the musculature. The overwhelming majority of ALS is sporadic in nature, while 10% of patients suffer from familial forms of disease, which have enabled the identification of causative genetic variants. ALS can be caused by mutations in genes that encode proteins involved in diverse cellular functions ranging from RNA metabolism, proteostasis and cytoskeletal homeostasis. Recent genetic studies have highlighted NIMA-related kinase 1 (NEK1) as a major genetic contributor to ALS. Loss-of-function genetic variants in NEK1 confer susceptibility to ALS in as many as 2% of all cases. The specific role and function of NEK1 in the CNS remains unresolved. What also remains elusive is the cellular mechanisms that lead to mutant NEK1 ALS pathophysiology. In the present study, we will use NEK1 cellular models, induced pluripotent stem cell (iPSC) patient-derived MNs, in vivo Drosophila models and ALS-NEK1 postmortem patient CNS tissue to: a) determine the mechanisms by which ALS-associated mutations impair MN function; b) characterize the physiological substrates for NEK1-dependent phosphorylation; and, c) validate the contribution of these changes towards neuropathology in ALS. We will test the hypothesis that NEK1 mutations cause neurotoxicity by disrupting the regulatory role of the kinase on cellular pathways that are essential for MN function. In preliminary experiments, we found that NEK1-deficient iPSC-derived MNs exhibit disrupted microtubule (MT) dynamics and impaired nuclear import. In Aim 1 we will determine whether these defects are relevant in the context of an extensive set of nonsense and missense ALS-associated NEK1 variants. In preliminary experiments, we found that NEK1 interactors are enriched for function in the MT cytoskeleton and nuclear import and that reduction of NEK1 levels results in differential expression of proteins involved in these pathways. In Aim 2 we will determine the physiological substrates for NEK1 phosphorylation in MNs by conducting phosphoproteomic mass spectrometry analysis and interrogating the functional effects of differential phosphorylation. In preliminary experiments we identified Niki as the closest Drosophila homologue of NEK1 and using RNAi lines we found that it is essential for motor function and survival. In Aim 3 we will determine the function of NEK1 in the intact nervous system of flies and validate our findings on the effects of the cellular models in vivo. Our studies will shed light into the cellular mechanisms that are compromised by mutant NEK1 in neurons and will likely uncover potential therapeutic targets for a significant percentage of ALS/FTD patients.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $759,016 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/8/2025	NON-COMPETING CONTINUATION	$759,016
														Subtotal = $759,016

Issue Date FY: 2024 ( Subtotal = $751,016 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	7/22/2024	NON-COMPETING CONTINUATION	$22,530
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/8/2024	NON-COMPETING CONTINUATION	$728,486
														Subtotal = $751,016

Issue Date FY: 2023 ( Subtotal = $766,016 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/6/2023	NEW	$766,016
														Subtotal = $766,016

Grand Total All Awards = $2,276,048

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Investigating the Contribution of ALS/FTD-Associated Mutations in the NEK1 Kinase to Disease Pathophysiology

Award Number: R01NS134166

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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