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Polyalanine Tails: A Novel Type of Protein Modification Implicated in Neurodegeneration

Award Number: R01NS102414
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: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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View Award Description

Polyalanine Tails: A Novel Type of Protein Modification Implicated in Neurodegeneration - Among the costliest diseases to society, and with rising prevalence in an aging population, neurodegenerative diseases pose a public health challenge. However, there are few options available for their treatment, and without pathomechanisms being sufficiently elucidated, one's ability to generate a rationale for interventions is greatly limited. Our studies are expected to address this barrier by establishing new etiological factors and molecular mechanisms of mammalian neurodegeneration. One such mechanism is Ribosome-associated Quality Control (RQC), that mediates the degradation of incomplete polypeptides produced by ribosomes that stall during translation. Key factors working in RQC are the Ltn1/Listerin E3 ubiquitin ligase and its partner, NEMF (Rqc2 in yeast). PI Joazeiro has previously found that Ltn1 mutation causes neurodegeneration in mice. PI Cox has more recently identified two independent mutations in mouse Nemf causing motor neuron disease and used this to knowledge to identify previously undiagnosed patients with a similar neuromuscular condition that inherited causative mutations in the human NEMF gene. In several ways, Ltn1-ENU and Nemf-ENU mice phenocopy each other, thus strengthening the connection between RQC dysfunction and neurodegeneration. The proposed studies are aimed at understanding molecular mechanisms underlying neurodegeneration caused by NEMF loss of function. We focus our analyses on a recently-discovered activity of NEMF that is conserved from bacteria to humans–the modification of aberrant nascent chains with C-terminal Alanine tails that have a proteolytic function. Based on our preliminary data, we hypothesize that NEMF-mediated Ala tailing protects neurons against degeneration. Results of these studies are expected to provide critical understanding of how defects in protein quality control lead to neurological disease.


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: 2026 ( Subtotal = $732,471 )
2026	2026	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	6/19/2026	NON-COMPETING CONTINUATION	$732,471
														Subtotal = $732,471

Issue Date FY: 2025 ( Subtotal = $735,524 )
2025	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	5/22/2025	NON-COMPETING CONTINUATION	$735,524
														Subtotal = $735,524

Issue Date FY: 2024 ( Subtotal = $717,158 )
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	5/22/2024	NON-COMPETING CONTINUATION	$717,158
2024	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	1/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $717,158

Issue Date FY: 2023 ( Subtotal = $732,174 )
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	5/12/2023	NON-COMPETING CONTINUATION	$732,174
2023	2022	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	11/28/2022	COMPETING CONTINUATION	$1
2023	2021	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/28/2022	NON-COMPETING CONTINUATION	-$1
														Subtotal = $732,174

Issue Date FY: 2022 ( Subtotal = $751,212 )
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	5/23/2022	COMPETING CONTINUATION	$751,212
														Subtotal = $751,212

Issue Date FY: 2021 ( Subtotal = $662,384 )
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/22/2021	NON-COMPETING CONTINUATION	$662,384
														Subtotal = $662,384

Issue Date FY: 2020 ( Subtotal = $662,384 )
2020	2020	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/17/2020	NON-COMPETING CONTINUATION	$662,384
														Subtotal = $662,384

Issue Date FY: 2019 ( Subtotal = $659,497 )
2019	2019	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/8/2019	NON-COMPETING CONTINUATION	$659,497
														Subtotal = $659,497

Issue Date FY: 2018 ( Subtotal = $659,497 )
2018	2018	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/9/2018	NON-COMPETING CONTINUATION	$659,497
														Subtotal = $659,497

Issue Date FY: 2017 ( Subtotal = $678,247 )
2017	2017	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/1/2017	NEW	$678,247
														Subtotal = $678,247

Grand Total All Awards = $6,990,548

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Polyalanine Tails: A Novel Type of Protein Modification Implicated in Neurodegeneration

Award Number: R01NS102414

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: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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