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Investigating a neuroprotective role of GBA in astrocytes

Award Number: R21NS118476
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: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Investigating a neuroprotective role of GBA in astrocytes - A key feature of Parkinson’s disease (PD) is abnormal protein aggregation within neurons in the brain. These neuronal protein aggregates spread throughout the nervous system as PD progresses, but how this occurs remains unclear. Recent work suggests that astrocytes, which support neuronal function by providing energy and protection from cellular stressors, may also have a neuroprotective role in PD and other neurodegenerative diseases. This proposal investigates a potential new role for the gene GBA, a common genetic risk factor for PD that is also associated with faster disease progression. While most studies of GBA focus exclusively on its role in neurons, we will test whether GBA is required in astrocytes to uptake and degrade neuronal-derived proteins in the extracellular matrix to reduce propagation of pathogenic neuronal protein aggregates. Our recent work using our Drosophila GBA deficient model (GBAdel) of PD indicates that exosomes are an important vehicle mediating the spread of protein aggregation. GBA deficiency dysregulates exosome formation, fusion, and/or content. Surprisingly, we found that glial expression of wildtype GBA can reduce protein aggregation present in GBAdel fly brains. To further investigate a possible neuroprotective role for GBA in astrocytes, we will use cultured neurons and astrocytes differentiated from human induced pluripotent stem cells generated from PD patients carrying GBA mutations. Unrelated healthy age- and sex-matched control and isogenic controls generated by CRISPR/Cas9 reversion of the GBA mutation to wildtype will be used as controls. We will first determine whether GBA is important for astrocyte uptake and processing of neuronal-derived EVs by examining GBA PD versus control astrocyte uptake and intracellular trafficking of neuronal EVs containing synuclein-GFP fusion protein. We will then test whether GBA has a neuroprotective role in astrocytes by co- culturing GBA PD or control astrocytes with GBA PD or control neurons and examine protein aggregation, endolysosomal trafficking and cell survival in both cell types. The results from this study could uncover new therapeutic targets to enhance the neuroprotective function of astrocytes, leading to treatments that could slow or halt the progression of PD and other neurodegenerative diseases characterized by protein aggregates.


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 = -$980 )
2025	2023	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/26/2025	NON-COMPETING CONTINUATION	-$980
														Subtotal = -$980

Issue Date FY: 2023 ( Subtotal = $170,250 )
2023	2023	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/26/2023	NON-COMPETING CONTINUATION	$170,250
														Subtotal = $170,250

Issue Date FY: 2022 ( Subtotal = $196,098 )
2022	2022	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/1/2022	NEW	$196,098
														Subtotal = $196,098

Grand Total All Awards = $365,368

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Investigating a neuroprotective role of GBA in astrocytes

Award Number: R21NS118476

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: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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