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Pathogenic ROle of the Novel Mitochondrial Apoptotic PSAP in ALS

Award Number: R21NS095256
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2019

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Pathogenic ROle of the Novel Mitochondrial Apoptotic PSAP in ALS - 1 Apoptosis of motor neurons is a well-documented feature in amyotrophic lateral sclerosis (ALS), and related 2 motor neuron diseases (MNDs). However, the role of programmed cell death (apoptosis) in the development of 3 these diseases remains unresolved. The goal of the proposed study is to determine the role of a novel 4 mitochondrial apoptotic protein, PSAP (presenilin-1 [PS1]- associated protein), in the development of ALS. 5 ALS is a fetal adult-onset neurodegenerative disease characterized by the death of motor neurons, axon 6 degeneration, and denervation at the neuromuscular junction. There is no cure for ALS owing to the fact that 7 the mechanisms underlying the development of the disease remain elusive. The majority of ALS is sporadic, 8 but approximately 10% of ALS cases are familial; of those, ~20% are attributed to mutations in the superoxide 9 dismutase 1 (SOD1) gene. The identification of SOD1 mutations in ALS has led to the development of animal 10 models of the disease to study the molecular pathogenesis in vivo. The most widely used ALS model is the 11 SOD1G93A mouse, which expresses human mutant SOD1G93A. Using this model, a recent study suggests that 12 death receptor 6 (DR6) is responsible for the apoptotic neurodegeneration observed in ALS. However, the 13 molecular mechanism for DR6 remains unknown. It is particularly interesting that the investigator's recent 14 study revealed that DR6 forms a complex with PSAP. Investigator-produced data further demonstrated that 15 knockdown of PSAP blocked DR6-induced apoptosis, suggesting that PSAP is crucial in DR6-mediated 16 apoptotic signaling. Recently, the investigator generated a PSAP-knockout mouse model and found that axons 17 of sensory neurons isolated from the spinal cord of these mice were resistant to apoptosis induced by 18 withdrawal of nerve growth factor (NGF), similar to the result of inactivation of DR6. Also, preliminary data from 19 cross breeding PSAP-knockout and SOD1G93A mice showed, promisingly, that PSAP knockout greatly 20 improved motor neuron function in SOD1G93A mice. These findings led to the hypothesis that the DR6-PSAP- 21 mediated apoptotic-signaling pathway contributes to the development of ALS. This hypothesis will be tested by 22 two objectives. (1): Determine the role of PSAP in DR6-regulated apoptosis in vitro. These experiments 23 will be carried out using siRNA and co-immunoprecipitation approaches. (2): Determine the role of PSAP in 24 mediating the pathogenic effects of SOD1G93A using a novel PSAP-knockout mouse model and 25 SOD1G93A mice. Significance: Our novel finding that knockout of the apoptotic mitochondrial protein PSAP 26 greatly impromed motor neuron function in ALS SOD1G93A mouse provides a new avenue for studying the 27 mechanism underlying ALS pathogenesis. Specifically, our finding that knockout of PSAP restored the walking 28 ability and the control of incontinence in SOD1G93A mice raises the possibility that understanding the molecular 29 mechanism by which PSAP contributes to the pathogenesis of ALS may lead to the identification of novel 30 therapeutic target and development of methods of treatment to improve the quality of life of human 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: 2022 ( Subtotal = -$7,357 )
2022	2017	UNIVERSITY OF TEXAS OF THE PERMIAN BASIN	4901 E UNIVERSITY BLVD	ODESSA	TX	79762	ECTOR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$7,357
														Subtotal = -$7,357

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2017	UNIVERSITY OF TEXAS OF THE PERMIAN BASIN	4901 E UNIVERSITY BLVD	ODESSA	TX	79762	ECTOR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/9/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2017	UNIVERSITY OF TEXAS OF THE PERMIAN BASIN	4901 E UNIVERSITY BLVD	ODESSA	TX	79762	ECTOR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/23/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = -$1 )
2018	2017	UNIVERSITY OF TEXAS OF THE PERMIAN BASIN	4901 E UNIVERSITY BLVD	ODESSA	TX	79762	ECTOR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	7/16/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$76,617
2018	2017	UNIVERSITY OF TENNESSEE	1331 CIR PARK DR	KNOXVILLE	TN	37916	KNOX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/16/2018	NON-COMPETING CONTINUATION	-$76,617
2018	2017	UNIVERSITY OF TENNESSEE	1331 CIR PARK DR	KNOXVILLE	TN	37916	KNOX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	9/16/2018	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2017 ( Subtotal = $183,750 )
2017	2017	UNIVERSITY OF TENNESSEE	1331 CIR PARK DR	KNOXVILLE	TN	37916	KNOX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/17/2017	NON-COMPETING CONTINUATION	$183,750
														Subtotal = $183,750

Issue Date FY: 2016 ( Subtotal = $220,500 )
2016	2016	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/16/2016	NEW	$220,500
														Subtotal = $220,500

Grand Total All Awards = $396,892

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Pathogenic ROle of the Novel Mitochondrial Apoptotic PSAP in ALS

Award Number: R21NS095256

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2019

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