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Defining the role of C. elegans Parkin/PDR-1 in glial engulfment of neuron fragments

Award Number: F31NS118958
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2022

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Defining the role of C. elegans Parkin/PDR-1 in glial engulfment of neuron fragments - PROJECT SUMMARY Glia engulf fragments of live neurons in order to regulate specialized neuron endings1,2. Amounting evidence indicates the engulfment of neuron fragments by glia is a broad regulatory and developmental function of glia in both the central and peripheral nervous systems. How this process is regulated under normal conditions is unclear in any system, but it was recently shown that mis-regulation of this process contributes to early synapse loss in mouse models of Alzheimer’s disease3. Furthermore, mis-regulation of phagocytosis by Retinal Pigment Epithelium cell in the eye may cause some forms of macular degeneration. Synapse loss and sensory disfunction are early hallmarks of Parkinson’s disease, however the involvement of glia is unknown4,5. Loss of function of the E3 ubiquitin ligase Parkin contributes to the onset and progression of Parkinson’s disease. The role of Parkin mediating mitophagy in neurons is well characterized in mammals and invertebrate models,6 but despite being expressed in several glial subtypes, the functions of Parkin in glia are unknown. We have recently shown in C. elegans that fragments of a specialized sensory neuron are engulfed by an associated glial cell. Preliminarily, I have found that loss of function of the Parkin ortholog pdr-1 elicits a substantial increase in the number neuron fragments engulfed by glia, demonstrating that PDR-1 inhibits engulfment by glia. C. elegans has historically been a powerful model used to unearth the mechanisms of phagocytosis by which cells recognize, engulf, and degrade cellular debris7. I propose to use this system to probe the mechanism by which Parkin/PDR-1 regulates glial phagocytosis of neuron fragments. I will determine the cell-specific requirements of PDR-1, probe substrates of its E3 ligase activity that may have roles in glial engulfment, and finally ask if its role in mitophagy has a function in glial engulfment.


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: 2023 ( Subtotal = -$23,551 )
2023	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	6/20/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$6,228
2023	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	5/15/2023	NON-COMPETING CONTINUATION	-$1
2023	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/24/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$13,176
2023	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	5/15/2023	NEW	-$4,146
														Subtotal = -$23,551

Issue Date FY: 2022 ( Subtotal = $42,375 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	6/8/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$42,374
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/8/2022	NON-COMPETING CONTINUATION	-$7,521
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/16/2022	NON-COMPETING CONTINUATION	$7,522
														Subtotal = $42,375

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/19/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $40,382 )
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/18/2020	NEW	$40,382
														Subtotal = $40,382

Grand Total All Awards = $59,206

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Defining the role of C. elegans Parkin/PDR-1 in glial engulfment of neuron fragments

Award Number: F31NS118958

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2022

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