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Compromised LDH activity causes motor deficits and hastens ALS progression

Award Number: R01AG013730
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/1996
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Compromised LDH activity causes motor deficits and hastens ALS progression - Motor axon loss is a cardinal symptom of motor neuron disorders including amyotrophic lateral sclerosis (ALS). Schwann cells (SCs) myelinate and provide trophic support to axons in the peripheral nervous system (PNS) and disruption of SC metabolism often leads to axon degeneration, both symptoms of peripheral neuropathy. The lactate shuttle hypothesis proposes that glycolytic glial support cells supply lactate to axons to sustain their high metabolic demands, a process that requires interconversion of lactate and pyruvate via lactate dehydrogenase (LDH) in both glia and neurons. To test this hypothesis in the PNS, we deleted LDH subunits LDHA and LDHB specifically in motor neurons (MNs), sensory neurons (SNs), or SCs. We find that LDH deletion in SCs or MNs leads to progressive degeneration of motor axons, whereas LDH loss in SNs causes no apparent abnormalities in sensory axons. These results support a model in which lactate shuttling from SCs selectively sustains motor but not sensory axons and suggest that LDH activity and lactate shuttling play a role in motor- dominated neuropathies such as ALS. Indeed, LDHB-deficient mice develop progressive motor dysfunction similar to ALS mouse models, and LDH deficiency synergizes with a slowly progressing ALS model to induce severe, early onset disease. In conjunction with these studies, we identified rare loss-of-function LDHB mutations in ALS patients. In this proposal, we outline experiments to examine the differential responses of MN and SN neurons to loss of LDH function to identify pathways involved in the observed selective motor axon degeneration. We will use a cellular complementation assay utilizing iPSC-derived neurons to dissect components involved in support of peripheral motor axons. We will use biochemical and cellular complementation assays to examine LDHB variants found in ALS patients and controls to determine if deleterious variants are enriched in ALS. We will study mice lacking specific LDH isoforms in defined cell types to determine the cells involved in motor axon metabolic support and the pathways they invoke to influence axon health. Additionally, we will use these LDH mutant mice to interrogate how compromised lactate/pyruvate metabolism interacts with other ALS risk factors to speed disease progression. Results of these studies will establish the relationship between LDH, lactate/pyruvate metabolism in the PNS, and development of motor neuron diseases including ALS, and stimulate development of new axo-protective therapeutics for these devastating disorders.


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 = $583,434 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Aging Research	000	24	1/9/2025	NON-COMPETING CONTINUATION	$583,434
														Subtotal = $583,434

Issue Date FY: 2024 ( Subtotal = $754,970 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Aging Research	002	23	6/14/2024	NON-COMPETING CONTINUATION	$64,827
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Aging Research	001	23	1/22/2024	NON-COMPETING CONTINUATION	$583,434
2024	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Aging Research	000	22	12/20/2023	COMPETING CONTINUATION	$106,709
														Subtotal = $754,970

Issue Date FY: 2023 ( Subtotal = $521,755 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Aging Research	000	22	4/19/2023	COMPETING CONTINUATION	$521,755
														Subtotal = $521,755

Issue Date FY: 2018 ( Subtotal = -$2,647 )
2018	2016	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Aging Research	001	20	11/6/2017	SUPPLEMENT FOR EXPANSION	$27
2018	2016	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Aging Research	002	20	11/7/2017	SUPPLEMENT FOR EXPANSION	-$2,647
2018	2015	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Aging Research	000	20	11/6/2017	NON-COMPETING CONTINUATION	-$27
														Subtotal = -$2,647

Issue Date FY: 2016 ( Subtotal = $353,314 )
2016	2016	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Aging Research	000	20	9/1/2016	SUPPLEMENT FOR EXPANSION	$353,314
														Subtotal = $353,314

Issue Date FY: 2015 ( Subtotal = $505,321 )
2015	2015	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Aging Research	000	20	6/30/2015	NON-COMPETING CONTINUATION	$505,321
														Subtotal = $505,321

Issue Date FY: 2014 ( Subtotal = $516,992 )
2014	2014	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Aging Research	000	19	6/24/2014	NON-COMPETING CONTINUATION	$516,992
														Subtotal = $516,992

Issue Date FY: 2013 ( Subtotal = $488,558 )
2013	2013	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Aging Research	000	18	7/15/2013	NON-COMPETING CONTINUATION	$488,558
														Subtotal = $488,558

Issue Date FY: 2012 ( Subtotal = $516,992 )
2012	2012	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Aging Research	000	17	6/20/2012	NON-COMPETING CONTINUATION	$516,992
														Subtotal = $516,992

Issue Date FY: 2011 ( Subtotal = $516,990 )
2011	2011	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Aging Research	001	16	8/18/2011	COMPETING CONTINUATION	$516,990
2011	2010	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Aging Research	000	15	8/16/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $516,990

Issue Date FY: 2010 ( Subtotal = $574,148 )
2010	2010	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Aging Research	000	15	6/24/2010	NON-COMPETING CONTINUATION	$574,148
														Subtotal = $574,148

Issue Date FY: 2009 ( Subtotal = $563,052 )
2009	2009	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Aging Research	000	14	7/2/2009	NON-COMPETING CONTINUATION	$563,052
														Subtotal = $563,052

Issue Date FY: 2008 ( Subtotal = $546,654 )
2008	2008	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Aging Research	000	13	6/20/2008	NON-COMPETING CONTINUATION	$546,654
														Subtotal = $546,654

Issue Date FY: 2007 ( Subtotal = $541,564 )
2007	2007	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Aging Research	000	12	7/26/2007	NON-COMPETING CONTINUATION	$541,564
														Subtotal = $541,564

Issue Date FY: 2006 ( Subtotal = $543,272 )
2006	2006	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Aging Research	000	11	8/31/2006	COMPETING CONTINUATION	$543,272
														Subtotal = $543,272

Issue Date FY: 2005 ( Subtotal = $438,312 )
2005	2005	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Aging Research	000	10	6/8/2005	NON-COMPETING CONTINUATION	$438,312
														Subtotal = $438,312

Issue Date FY: 2004 ( Subtotal = $427,635 )
2004	2004	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Aging Research	000	9	6/4/2004	NON-COMPETING CONTINUATION	$427,635
														Subtotal = $427,635

Issue Date FY: 2003 ( Subtotal = $417,268 )
2003	2003	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Aging Research	000	8	6/11/2003	NON-COMPETING CONTINUATION	$417,268
														Subtotal = $417,268

Issue Date FY: 2002 ( Subtotal = $407,158 )
2002	2002	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Aging Research	000	7	6/26/2002	NON-COMPETING CONTINUATION	$407,158
														Subtotal = $407,158

Issue Date FY: 2001 ( Subtotal = $396,779 )
2001	2001	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Aging Research	000	6	5/28/2001	COMPETING CONTINUATION	$396,779
														Subtotal = $396,779

Issue Date FY: 2000 ( Subtotal = $375,238 )
2000	2000	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Aging Research	000	5	7/28/2000	NON-COMPETING CONTINUATION	$375,238
														Subtotal = $375,238

Issue Date FY: 1999 ( Subtotal = $362,733 )
1999	1999	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Aging Research	000	4	6/3/1999	NON-COMPETING CONTINUATION	$362,733
														Subtotal = $362,733

Issue Date FY: 1998 ( Subtotal = $350,713 ) (Continued on the next page)
Grand Total All Awards = $10,700,205

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Compromised LDH activity causes motor deficits and hastens ALS progression

Award Number: R01AG013730

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/1996

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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