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Determining the mechanism of alpha-synuclein dependent innate immune responses in the brain

Award Number: R01NS123431
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Determining the mechanism of alpha-synuclein dependent innate immune responses in the brain - Project Summary The nervous system was traditionally thought to act independently of an organism’s immune response and be an “immune privileged site”. Increasing scientific evidence has shown that the nervous system is not immune privileged but instead has a unique immune response that is critical for maintaining homeostasis and critical for central nervous system (CNS) function. Much of the work in the field of neuroinflammation has focused on the function of microglia, but little is known about the role of neurons in modulating neuroinflammatory responses in the CNS. Five years ago, we discovered that the neuronal protein, alpha-synuclein(asyn), was critical in protecting neurons from viral infection. We have extended these data to show that ayn modulates type 1 interferon (T1IFN) signaling. Asyn is known as a cause of Parkinson’s disease (PD) and is known to be dysregulated in neurodegenerative diseases, traumatic brain injury, and other diverse CNS diseases. Despite the importance of asyn in CNS disease states, the functional role of asyn expression is not well understood. We have discovered that asyn expression is necessary to support expression of specific interferon stimulated genes (ISGs) in the brain during T1IFN signaling, independent of microglia activation. Using induced pluripotent stem cells (iPSC) and CRISPR-mediated SNCA deletion to create asyn KO human dopaminergic neurons, we found that viral growth in neurons is inhibited in the presence of asyn expression and that viral- induced ISGs such as IFIT1, OAS1, and TRIM25 exbibit decreased expression in asyn KO neurons. We next found that asyn KO neurons exhibit a broad loss of ISG expression following treatment with poly I:C or type 1 interferon (2) treatment due to loss of asyn-dependent STAT2 activation and asyn nuclear localization. Taken together, our data show for the first time that asyn functions to support interferon responses in neurons. The goal of this proposal is to determine the specific mechanism of asyn-dependent innate immune responses in neurons. We hypothesize that asyn is a novel neuron-intrinsic regulator of the CNS innate immune response. We will test our hypothesis in three aims. Aim 1 will use asyn KO and WT human neurons to define the specific interactions between asyn, interferon signaling, and vesicle transport in neurons. Aim 2 will define the role of neuron-intrinsic asyn production on the innate T-cell response in the brain using an inducible, nestin-Cre-lox knockout of the asyn gene (Snca) in mice. Aim 3 will evaluate PD-specific and species specific changes in asyn that may influence its native function in neurons. Taken together, the proposed studies will significantly advance our understanding of neuron-intrinsic control of the innate immune response in the CNS and provide novel insight into the underlying immunopathogenesis that contributes to diverse human diseases of the CNS.


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 = $300,395 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	4/29/2025	NON-COMPETING CONTINUATION	$300,395
2025	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/12/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$35,753
2025	2023	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/12/2025	NON-COMPETING CONTINUATION	-$35,753
														Subtotal = $300,395

Issue Date FY: 2024 ( Subtotal = $307,383 )
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$307,383
2024	2023	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $307,383

Issue Date FY: 2023 ( Subtotal = $397,039 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/4/2023	NON-COMPETING CONTINUATION	$397,039
														Subtotal = $397,039

Issue Date FY: 2022 ( Subtotal = $397,039 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/11/2022	NEW	$397,039
														Subtotal = $397,039

Grand Total All Awards = $1,401,856

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Determining the mechanism of alpha-synuclein dependent innate immune responses in the brain

Award Number: R01NS123431

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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