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Mimicking synuclein toxicity in plant cells to identify novel neuroprotective leads

Award Number: R44NS108804
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: 09/01/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Mimicking synuclein toxicity in plant cells to identify novel neuroprotective leads - Abstract A general mechanism for neurodegeneration, including Parkinson's disease and Alzheimer's dementia, is the breakdown and subsequent aggregation of misfolded neuronal proteins. In the “synucleinopathies” for example neurotoxicity is associated with the cleavage of mis-folded alpha-synuclein (ASYN), probably mainly by asparagine endopeptidase (AEP) [Zhang et al 2017]. This generates neurotoxic peptides that then aggregate with ASYN in lysosomes, forming the Lewy inclusion bodies associated with neurodegeneration. A very similar mechanism exists in plant cells in which plant AEP breaks down misfolded proteins to produce vacuolar aggregates associated with programmed cell death (PCD) [Hatsugai et al, 2015]. However, plants do not contain ASYN, so, in order to mimic ASYN toxicity, plant cells were transformed to express the misfolding- prone A53T variant of human ASYN (phase I). Thymoquinone was then used to trigger plant PCD [Hassanien et al 2013] and the plant cells expressing ASYN-A53T were shown to be significantly more susceptible to this toxicity than controls. In phase II a mutant population of these transgenic (ASYN) plant cells will be selected for survival under this procedure. This is an example of “target-directed evolution” in which mutants that survive selection should “evolve” toward increased biosynthesis of metabolites that inhibit AEP and/or ASYN toxicity. Individual mutant plant cell clones with ASYN-protective activity will be identified by screening extracts of resistant cultures, and micro-analytical methods [Kelley et al, 2019] will then be used to identify active metabolites as leads. Lobelia cardinalis cell cultures were used in phase I because we had previously transformed these with the human dopamine transporter gene to mimic MPP+-induced dopaminergic neurotoxicity [Brown et al 2016]. In phase II we will also use the medicinal plant, Polygonum multiflorum, which contains a stilbene that inhibits ASYN toxicity [Zhang et al 2018]. Phase II aims to identify novel leads that engage the AEP and ASYN targets, and to test the most promising of these in cellular and animal models of synucleinopathy. Leads will be developed with the University of Kentucky Parkinson's Disease Research Center and a pharmaceutical partner. Identification of leads that engage these targets will also support target- directed evolution in mutant plant cells as a commercial platform for drug discovery.


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: 2024 ( Subtotal = $0 )
2024	2022	NAPROGENIX INC	145 GRAHAM AVE	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	NAPROGENIX INC	145 GRAHAM AVE	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/16/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $617,512 )
2022	2022	NAPROGENIX INC	145 GRAHAM AVE	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/19/2022	NON-COMPETING CONTINUATION	$617,512
														Subtotal = $617,512

Issue Date FY: 2021 ( Subtotal = $617,521 )
2021	2021	NAPROGENIX, INC.	UK-ASTECC 145 GRAHAM AVE	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	8/13/2021	NON-COMPETING CONTINUATION	$617,521
2021	2020	NAPROGENIX, INC.	UK-ASTECC 145 GRAHAM AVE	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	10/27/2020	COMPETING CONTINUATION	$0
														Subtotal = $617,521

Issue Date FY: 2020 ( Subtotal = $624,004 )
2020	2020	NAPROGENIX, INC.	UK-ASTECC 145 GRAHAM AVE	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	9/20/2020	COMPETING CONTINUATION	$624,004
														Subtotal = $624,004

Grand Total All Awards = $1,859,037

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Mimicking synuclein toxicity in plant cells to identify novel neuroprotective leads

Award Number: R44NS108804

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: 09/01/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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