A mutation in the PRKAR1B gene drives pathological mechanisms of neurodegeneration across species

Tal Benjamin-Zukerman; Gilat Shimon; Marie E Gaine; Anwar Dakwar; Netta Peled; Mohammad Aboraya; Ashar Masri-Ismail; Rania Safadi-Safa; Meir Solomon; Varda Lev-Ram; Robert A Rissman; Johanna E Mayrhofer; Andrea Raffeiner; Merel O Mol; Benney M R Argue; Shaylah McCool; Binh Doan; John van Swieten; Eduard Stefan; Ted Abel; Ronit Ilouz

doi:10.1093/brain/awae154

Back

A mutation in the PRKAR1B gene drives pathological mechanisms of neurodegeneration across species

Journal article

Open access

Peer reviewed

A mutation in the PRKAR1B gene drives pathological mechanisms of neurodegeneration across species

Tal Benjamin-Zukerman, Gilat Shimon, Marie E Gaine, Anwar Dakwar, Netta Peled, Mohammad Aboraya, Ashar Masri-Ismail, Rania Safadi-Safa, Meir Solomon, Varda Lev-Ram, …

Brain (London, England : 1878), Vol.147(11), pp.3890-3905

11/04/2024

DOI: 10.1093/brain/awae154

PMCID: PMC11531844

PMID: 38743596

Files and links (1)

url

https://doi.org/10.1093/brain/awae154View

Published (Version of record) Open Access

Abstract

Protein Kinase A (PKA) neuronal function is controlled by the interaction of a regulatory (R) subunit dimer to two catalytic (C) subunits. Recently, the L50R variant in the gene encoding the RIβ subunit was identified in individuals with a novel neurodegenerative disease. However, the mechanisms driving the disease phenotype remained unknown. In this study, we generated a mouse model carrying the RIβ-L50R mutation to replicate the human disease phenotype and study its progression with age. We examined postmortem brains of affected individuals as well as live cell cultures. Employing biochemical assays, immunohistochemistry, and behavioral assessments, we investigated the impact of the mutation on PKA complex assembly, protein aggregation and neuronal degeneration. We reveal that RIβ is an aggregation-prone protein that progressively accumulates in wildtype and Alzheimer's mouse models with age, while aggregation is accelerated in the RIβ-L50R mouse model. We define RIβ-L50R as a causal mutation driving an age-dependent behavioral and disease phenotype in human and mouse models. Mechanistically, this mutation disrupts RIβ dimerization, leading to aggregation of its monomers. Intriguingly, interaction with the C-subunit protects the RIβ-L50R from self-aggregating, in a dose-dependent manner. Furthermore, cAMP signaling induces RIβ-L50R aggregation. The pathophysiological mechanism elucidated here for a newly recognized neurodegenerative disease, in which protein aggregation is the result of disrupted homodimerization, sheds light on a remarkably under-appreciated but potentially common mechanism across several neurodegenerative diseases.

Neurodegenerative Diseases

protein kinase A (PKA)

PRKAR1B

NLPD-PKA disease

protein aggregation

neuronal loss

Details

Title: Subtitle: A mutation in the PRKAR1B gene drives pathological mechanisms of neurodegeneration across species
Creators: Tal Benjamin-Zukerman - Bar-Ilan University
Gilat Shimon - Bar-Ilan University
Marie E Gaine - University of Iowa, Iowa Neuroscience Institute
Anwar Dakwar - Bar-Ilan University
Netta Peled - Bar-Ilan University
Mohammad Aboraya - Bar-Ilan University
Ashar Masri-Ismail - Bar-Ilan University
Rania Safadi-Safa - Bar-Ilan University
Meir Solomon
Varda Lev-Ram - University of California San Diego
Robert A Rissman
Johanna E Mayrhofer - Universität Innsbruck
Andrea Raffeiner - Universität Innsbruck
Merel O Mol - Erasmus MC
Benney M R Argue - University of Iowa
Shaylah McCool - University of Iowa
Binh Doan - University of Iowa
John van Swieten
Eduard Stefan - Universität Innsbruck
Ted Abel - University of Iowa, Iowa Neuroscience Institute
Ronit Ilouz - Bar-Ilan University
Resource Type: Journal article
Publication Details: Brain (London, England : 1878), Vol.147(11), pp.3890-3905
DOI: 10.1093/brain/awae154
PMID: 38743596
PMCID: PMC11531844
NLM abbreviation: Brain
ISSN: 0006-8950
eISSN: 1460-2156
Publisher: Oxford University Press; OXFORD
Grant note: Israel Science Foundation: 1706/22 United States-Israel Binational Science Foundation: 2019270 Israel Cancer Research Fund: 22-203-RCDA Roy J. Carver Charitable Trust as the Chair of Neuroscience: R01 MH117964R01 MH117964 NIH: P50 HD 103556 Pilot grant, EHSRC P30 Center Grant: NIH ES005605 Austrian Science Fund: FWF P30441, P32960, P35159
R.I. was supported by the Israel Science Foundation (grant number 1706/22). R.I. and T.A. were supported by a United States-Israel Binational Science Foundation (Grant number 2019270). This study was supported by Research Career Development Award to R.I. from the Israel Cancer Research Fund (Award ID: 22-203-RCDA). T.A. was supported by the Roy J. Carver Charitable Trust as the Chair of Neuroscience., an R01 supplement (R01 MH117964; T.A.-Contact and K. Diba), and a P50 Center grant (University of Iowa Hawkeye Intellectual and Developmental Disability Research Center; NIH P50 HD 103556; T.A. and L. Strathearn- MultiPIs). M.E.G. was supported by a pilot grant as part of the EHSRC P30 Center Grant (NIH ES005605). E.S. was supported by grants from the Austrian Science Fund (FWF P30441, P32960, P35159).
Language: English
Electronic publication date: 05/14/2024
Date published: 11/04/2024
Academic Unit: Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
Record Identifier: 9984625756902771

Metrics

19 Record Views

6 Times Cited - Web of Science