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The role of a-synuclein accumulation in lysosomal hydrolase trafficking and function

Award Number: R01NS092823
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: 08/01/2015
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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The role of a-synuclein accumulation in lysosomal hydrolase trafficking and function - Abstract The aggregation of a-Synuclein (a-syn) into insoluble fibrils plays a key role in the pathogenesis of Dementia with Lewy bodies (DLB), Parkinson’s disease (PD) and other synucleinopathies. Despite the documentation of a-synuclein as a component of Lewy body inclusions for over 25 years, there remains a significant knowledge gap in the mechanisms that causally link protein aggregates to neurodegeneration. Recent genetic studies have implicated the lysosomal degradation system into the pathogenesis of DLB and PD. Among the strongest genetic risk factors are loss-of-function mutations lysosomal β-glucocerebrosidase (GCase) encoded by GBA1, indicating that compromised lysosomal function may play a direct role in neurodegeneration. During our previous funding period, we found that a-syn aggregates are initiated inside lysosomes by interacting with glycosphingolipid substrates that accumulate upon loss of GCase. Once formed, these aggregates perturb multiple, essential branches of the proteostasis pathway, including the folding in the endoplasmic reticulum (ER) and post-ER trafficking at the cis-Golgi. This further augments a-syn aggregation, creating a self-propagating pathogenic cycle. The previous funding period uncovered novel mechanisms and biological targets that enhance the trafficking of hydrolases and lysosomal function. Here, we will build on our previous work to examine how a- syn aggregates perturb protein folding in the ER, N-linked glycosylation in the ER, and the downstream effect on lysosomal function. We will develop novel molecules to restore these key proteostasis pathways. Our studies will employ a combination of patient-derived PD iPSC-neuron cultures, synucleinopathy mouse models, and human brain. We previously found that a-syn accumulation in PD patient neurons induced ER fragmentation and concealed the cell’s ability to recognize misfolded proteins in the ER, resulting in aggregation of immature GCase. Since misfolded proteins in the ER are usually recognized by the unfolded protein response (UPR), in aim 1, we will examine the link between the UPR, GCase solubility, and trafficking to the lysosome. We will determine if triggering the UPR in PD can restore lysosomal function and reduce a-syn. In aim 2, we will test the hypothesis that reduced glucose flux and protein N-glycosylation of GCase and other hydrolases contributes to lysosomal depletion and dysfunction in PD. In aim 3, we will build upon our prior studies, which showed that lysosomal function can be rescued by enhancing the SNARE protein ykt6. We will test novel small molecule activators of the ykt6-lysosomal biogenesis pathway in vitro and in vivo. By studying basic biology mechanisms of protein trafficking, we have a unique opportunity to link essential cellular proteostasis pathways to disease pathogenesis. Our studies may impact the field by discovering novel pathogenic mechanisms, identifying new biological targets, and further develop therapies to enhance lysosomal biogenesis to restore proteostasis in PD and DLB.


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 = $618,542 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	7/17/2025	NON-COMPETING CONTINUATION	$618,542
														Subtotal = $618,542

Issue Date FY: 2024 ( Subtotal = $618,542 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	5/17/2024	NON-COMPETING CONTINUATION	$0
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	4/8/2024	NON-COMPETING CONTINUATION	$618,542
														Subtotal = $618,542

Issue Date FY: 2023 ( Subtotal = $618,542 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	5/12/2023	NON-COMPETING CONTINUATION	$618,542
														Subtotal = $618,542

Issue Date FY: 2022 ( Subtotal = $618,542 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	7/5/2022	COMPETING CONTINUATION	$618,542
2022	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $618,542

Issue Date FY: 2019 ( Subtotal = $337,969 )
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/24/2019	NON-COMPETING CONTINUATION	$337,969
														Subtotal = $337,969

Issue Date FY: 2018 ( Subtotal = $337,969 )
2018	2018	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/26/2018	NON-COMPETING CONTINUATION	$337,969
														Subtotal = $337,969

Issue Date FY: 2017 ( Subtotal = $337,969 )
2017	2017	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/7/2017	NON-COMPETING CONTINUATION	$337,969
														Subtotal = $337,969

Issue Date FY: 2016 ( Subtotal = $337,969 )
2016	2016	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/24/2016	NON-COMPETING CONTINUATION	$337,969
														Subtotal = $337,969

Issue Date FY: 2015 ( Subtotal = $337,969 )
2015	2015	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/22/2015	NEW	$337,969
														Subtotal = $337,969

Grand Total All Awards = $4,164,013

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The role of a-synuclein accumulation in lysosomal hydrolase trafficking and function

Award Number: R01NS092823

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: 08/01/2015

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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