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Elucidating the etiology of SPAST-based Hereditary Spastic Paraplegia

Award Number: R01NS115977
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: 12/15/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Elucidating the etiology of SPAST-based Hereditary Spastic Paraplegia - PROJECT SUMMARY Hereditary Spastic Paraplegia (HSP) is a heritable neurodegenerative disorder in which patients suffer from progressive weakness, spasticity of lower limbs and gait deficiencies. The disease mainly manifests as adult- onset die-back degeneration of the corticospinal tracts (CSTs). SPAST, also called SPG4, encodes spastin, which is an enzyme that severs microtubules. By far, SPAST is the most common gene mutated in HSP. To date, haploinsufficiency resulting from reduced functional spastin levels has been the prevalent mechanistic explanation for HSP-SPG4. However, haploinsufficiency fails to explain why there are no developmental abnormalities in HSP patients and why axonal degeneration is mostly confined to the CSTs. In addition, SPG4 knockout (KO) mice display only very mild motor deficits, with no reports of CST die-back. A new mouse model in the laboratory of the PI has been designed specifically to test gain-of-function toxicity of mutant spastin proteins as the cause of CST die-back and HSP-like motor deficits. The central hypothesis of this proposal is that the toxic properties of mutant spastin proteins are the cause of HSP-SPG4, whereas reduced functional spastin levels do not cause HSP but render axons more vulnerable to the disease-specific hit. Mechanistic hypotheses will be investigated via transgenic mouse models (including a new mouse established in the PI’s laboratory, the SPAST knockout mouse, and the mouse that is generated by crossing the two), as well as forebrain glutamatergic neuronal cultures derived from isogenic human induced pluripotent stem cell (hiPSC) lines. Catwalk gait analyses and CST anatomical assessments on the mice will be conducted to compare and contrast the phenotypes resulting from toxicity of mutant spastins with those resulting from reduced functional spastin levels. The hypothesis will be tested that crossing the two mouse lines will result in a more extreme HSP- like phenotype than displayed by either of the parent lines. Dose dependent cytotoxicity of accumulated mutated spastin proteins, a key prediction of a gain-of-function mechanism for the disease, will be evaluated. Decreased microtubule acetylation observed in the afflicted axons is posited to result from higher histone deacetylase 6 (HDAC6) activity elicited by mutant spastins and is posited to be the main cause of the die-back degeneration of CSTs. Potential mechanistic explanations for the greater HDAC6 activity will be explored. Reduced microtubule mobility resulting from reduced microtubule severing (due to less functional spastin) is posited to be the main cause of the greater vulnerability of the axon to the mutant spastins. Contemporary molecular biological, live-cell imaging, anatomical and behavioral approaches will be used to test these hypotheses. Successful resolution of these issues will lead to better prospects for treating patients with HSP-SPG4, and also provide insights into microtubule-based mechanisms that may be common across HSPs caused by mutations of other genes.


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 = $340,875 )
2025	2025	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/27/2024	NON-COMPETING CONTINUATION	$340,875
														Subtotal = $340,875

Issue Date FY: 2024 ( Subtotal = $367,388 )
2024	2024	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/25/2024	NON-COMPETING CONTINUATION	$26,513
2024	2024	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/22/2023	NON-COMPETING CONTINUATION	$340,875
														Subtotal = $367,388

Issue Date FY: 2023 ( Subtotal = $378,750 )
2023	2023	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/7/2023	NON-COMPETING CONTINUATION	$37,875
2023	2023	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/17/2023	NON-COMPETING CONTINUATION	$340,875
														Subtotal = $378,750

Issue Date FY: 2022 ( Subtotal = $378,750 )
2022	2022	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/2/2021	NON-COMPETING CONTINUATION	$340,875
2022	2022	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/24/2022	NON-COMPETING CONTINUATION	$37,875
														Subtotal = $378,750

Issue Date FY: 2021 ( Subtotal = $378,021 )
2021	2021	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/15/2020	NEW	$378,021
														Subtotal = $378,021

Grand Total All Awards = $1,843,784

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Elucidating the etiology of SPAST-based Hereditary Spastic Paraplegia

Award Number: R01NS115977

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: 12/15/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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