Inosine monophosphate dehydrogenase intranuclear inclusions are markers of aging and neuronal stress in the human substantia nigra.

Cytoophidia Inosine monophosphate dehydrogenase Parkinson's disease Substantia nigra, aging, neurodegeneration

Journal

Neurobiology of aging
ISSN: 1558-1497
Titre abrégé: Neurobiol Aging
Pays: United States
ID NLM: 8100437

Informations de publication

Date de publication:
17 Nov 2023
Historique:
received: 22 08 2023
revised: 03 11 2023
accepted: 06 11 2023
medline: 23 11 2023
pubmed: 23 11 2023
entrez: 22 11 2023
Statut: aheadofprint

Résumé

We explored mechanisms involved in the age-dependent degeneration of human substantia nigra (SN) dopamine (DA) neurons. Owing to its important metabolic functions in post-mitotic neurons, we investigated the developmental and age-associated changes in the purine biosynthetic enzyme inosine monophosphate dehydrogenase (IMPDH). Tissue microarrays prepared from post-mortem samples of SN from 85 neurologically intact participants humans spanning the age spectrum were immunostained for IMPDH combined with other proteins. SN DA neurons contained two types of IMPDH structures: cytoplasmic IMPDH filaments and intranuclear IMPDH inclusions. The former were not age-restricted and may represent functional units involved in sustaining purine nucleotide supply in these highly metabolically active cells. The latter showed age-associated changes, including crystallization, features reminiscent of pathological inclusion bodies, and spatial associations with Marinesco bodies; structures previously associated with SN neuron dysfunction and death. We postulate dichotomous roles for these two subcellularly distinct IMPDH structures and propose a nucleus-based model for a novel mechanism of SN senescence that is independent of previously known neurodegeneration-associated proteins.

Identifiants

DOI: 10.1016/j.neurobiolaging.2023.11.005 PMID: 37992544
pubmed: 37992544
pii: S0197-4580(23)00260-9
doi: 10.1016/j.neurobiolaging.2023.11.005
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

43-56

Informations de copyright

Copyright © 2023 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declarations of interest none.

Auteurs

John Woulfe (J)

Neuroscience Program, The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada. Electronic address: jwoulfe@eorla.ca.

David G Munoz (DG)

Li Ka Shing Knowledge Institute & Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine, St. Michael's Hospital, Unity Health, University of Toronto, Toronto, Ontario, Canada.

Douglas A Gray (DA)

Center for Cancer Therapeutics, The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Hyder A Jinnah (HA)

Departments of Neurology, Human Genetics & Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.

Alyona Ivanova (A)

The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children and Neurosurgery Research Department, St. Michael's Hospital, Toronto Unity Health, Toronto, Ontario, Canada.

Classifications MeSH