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Determine how loss-of-function of the TBK1 kinase causes age-dependent degeneration in frontotemporal dementia

Award Number: F32AG059358
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2019

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Determine how loss-of-function of the TBK1 kinase causes age-dependent degeneration in frontotemporal dementia - PROJECT SUMMARY I propose to determine how loss-of-function of the TANK-binding kinase 1 (TBK1) kinase causes age- dependent degeneration in frontotemporal dementia (FTD), the second most frequent dementia after Alzheimer's disease. Heterozygous mutations were identified in the TBK1 gene as causative of familial and sporadic FTD and amyotrophic lateral sclerosis (ALS). Disease is likely to arise from haploinsufficiency as the majority of familial TBK1 mutations produce premature stop codons leading to non-sense mediated mRNA degradation. TBK1 is an IKK family kinase previously identified for a central role in controlling type- I interferon production in response to viral infection. It does this by phosphorylating interferon regulation factor 3 (IRF3), a transcription factor. TBK1 has also been implicated in regulating autophagy by its phosphorylation of the autophagy receptors optineurin (OPTN) and P62/SQSTM1, mutations in which cause FTD/ALS. Loss-of- function (LOF) variants in TBK1 causing FTD/ALS produce cytoplasmic TDP-43 aggregation, a hallmark of FTD instances without Tau or FUS pathology and in >95% of ALS. Patients that bear both a TBK1 mutation and another dominant disease-causing variant, such as GGGGCC repeat expansion of C9orf72 and point mutation in FUS, develop premature onset of ALS/FTD at ages of 40-50, suggesting that reduction in TBK1 activity may modulate aging of the central nervous system of synergize with other disease-causing mutation. In this proposal, I plan to conduct two independent but closely-related research aims to identify how TBK1 contributes to maintenance of a normal nervous system and how reduction in it contributes to age-dependent FTD and/or ALS. To identify mechanism(s) underlying toxicity in FTD and ALS mediated by reduced TBK1 activity, I will 1) determine whether TBK1 haploinsufficiency causes cognitive and/or motor deficits in aged mice; 2) determine whether reduction or deletion of TBK1 broadly from neurons across the brain causes cognitive or motor deficits; 3) determine whether deletion of TBK1 from motor neurons causes motor neuron deficits; 4) determine whether reduction in TBK1 kinase activity is a pathological feature of FTD (and ALS) in TDP-43, FUS, and C9orf72 mouse models; 5) determine whether toxicity from reduced TBK1 activity is non- cell autonomous using co-cultures of wild type, Tbk1+/-, or Tbk1-/- cortical neurons, astrocytes, and/or microglia. To identify the role of TBK1 in TDP-43 aggregation, I will 1) determine whether TBK1 kinase activity is activated by TDP-43 cytosolic aggregates 2) determine whether reduction in TBK1 or its activity affects clearance of TDP-43 aggregates, using an inducible TDP-43 aggregation system I have established in a neuronal cell line (SHSY5Y); 3) determine whether Tbk1 haploinsufficiency exacerbates deficits of TDP-43 transgenic mice.


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: 2022 ( Subtotal = -$1,664 )
2022	2019	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	2	4/22/2022	NON-COMPETING CONTINUATION	-$1,664
2022	2018	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	4/22/2022	NEW	$0
														Subtotal = -$1,664

Issue Date FY: 2020 ( Subtotal = -$13,689 )
2020	2019	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	2/21/2020	NON-COMPETING CONTINUATION	-$13,689
														Subtotal = -$13,689

Issue Date FY: 2019 ( Subtotal = $67,248 )
2019	2019	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	4/18/2019	NON-COMPETING CONTINUATION	$67,248
														Subtotal = $67,248

Issue Date FY: 2018 ( Subtotal = $62,483 )
2018	2018	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	002	1	6/15/2018	NEW	$1,972
2018	2018	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	1	3/7/2018	NEW	$0
2018	2018	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	3/7/2018	NEW	$60,511
														Subtotal = $62,483

Grand Total All Awards = $114,378

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Determine how loss-of-function of the TBK1 kinase causes age-dependent degeneration in frontotemporal dementia

Award Number: F32AG059358

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2019

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