Rotenone induces regionally distinct α-synuclein protein aggregation and activation of glia prior to loss of dopaminergic neurons in C57Bl/6 mice.

Autor: Rocha SM; Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, United States of America; Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States of America., Bantle CM; Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States of America., Aboellail T; Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, United States of America., Chatterjee D; Jefferson Comprehensive Parkinson's Center, Vickie & Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, United States of America., Smeyne RJ; Jefferson Comprehensive Parkinson's Center, Vickie & Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, United States of America., Tjalkens RB; Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States of America. Electronic address: ron.tjalkens@colostate.edu.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2022 Jun 01; Vol. 167, pp. 105685. Date of Electronic Publication: 2022 Mar 05.
DOI: 10.1016/j.nbd.2022.105685
Abstrakt: Rotenone is a naturally occurring insecticide that inhibits mitochondrial complex I and leads to neurochemical and neuropathological deficits closely resembling those in Parkinson's disease (PD). Deficits include loss of dopaminergic neurons (DAn) in the substantia nigra pars compacta (SNpc), decreased dopamine levels and aggregation of misfolded alpha-synuclein (p129). In rat models of rotenone-induced parkinsonism, the progression of neuronal injury has been associated with activation of microglia and astrocytes. However, these neuroinflammatory changes have been challenging to study in mice, in part because the systemic rotenone exposure model utilized in rats is more toxic to mice. To establish a reproducible murine model of rotenone-induced PD, we therefore investigated the progression of neuroinflammation, protein aggregation and DAn loss in C57Bl/6 mice by exposing animals to 2.5 mg/kg/day rotenone for 14 days, followed by a two-week period where neuroinflammation is allowed to progress. Our results indicate that initial cellular dysfunction leads to increased formation of proteinase K-resistant p129 aggregates in the caudate-putamen and SNpc. Clearance of these aggregates was region- and cell type-specific, with the early appearance of reactive astrocytes coinciding with accumulation of p129 in the SNpc. Phagocytic microglial cells containing p129 aggregates were observed proximal to p129 + DAn in the SNpc. The majority of neuronal loss in the SNpc occurred during the two-week period after rotenone exposure, subsequent to the peak of microglia and astrocyte activation, as well as the peak of p129 aggregation. A secondary peak of p129 coincided with neurodegeneration at later timepoints. These data indicate that systemic exposure to rotenone in C57Bl/6 mice causes progressive accumulation and regional spread of p129 aggregates that precede maximal loss of DAn. Thus, activation of glial cells and aggregation of p129 appear to drive neuronal loss following neurotoxic stress imposed by exposure to rotenone.
(Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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