Heat Shock Protein 70 as a Sex-Skewed Regulator of α-Synucleinopathy.

Autor: Bhatia TN; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA., Clark RN; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA., Needham PG; Dept. of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA., Miner KM; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA., Jamenis AS; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA., Eckhoff EA; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA., Abraham N; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA., Hu X; Dept. of Neurology, University of Pittsburgh, Pittsburgh, PA, USA., Wipf P; Dept. of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA., Luk KC; Dept. of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA., Brodsky JL; Dept. of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA., Leak RK; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA. leakr@duq.edu.
Jazyk: angličtina
Zdroj: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics [Neurotherapeutics] 2021 Oct; Vol. 18 (4), pp. 2541-2564. Date of Electronic Publication: 2021 Sep 15.
DOI: 10.1007/s13311-021-01114-6
Abstrakt: The role of molecular chaperones, such as heat shock protein 70 (Hsp70), is not typically studied as a function of biological sex, but by addressing this gap we might improve our understanding of proteinopathic disorders that predominate in one sex. Therefore, we exposed male or female primary hippocampal cultures to preformed α-synuclein fibrils in a model of early-stage Lewy pathology. We first discovered that two mechanistically distinct inhibitors of Hsp70 function increased phospho-α-synuclein + inclusions more robustly in male-derived neurons. Because Hsp70 is released into extracellular compartments and may restrict cell-to-cell transmission/amplification of α-synucleinopathy, we then tested the effects of low-endotoxin, exogenous Hsp70 (eHsp70) in primary hippocampal cultures. eHsp70 was taken up by and reduced α-synuclein + inclusions in cells of both sexes, but pharmacological suppression of Hsp70 function attenuated the inhibitory effect of eHsp70 on perinuclear inclusions only in male neurons. In 20-month-old male mice infused with α-synuclein fibrils in the olfactory bulb, daily intranasal eHsp70 delivery also reduced inclusion numbers and the time to locate buried food. eHsp70 penetrated the limbic system and spinal cord of male mice within 3 h but was cleared within 72 h. Unexpectedly, no evidence of eHsp70 uptake from nose into brain was observed in females. A trend towards higher expression of inducible Hsp70-but not constitutive Hsp70 or Hsp40-was observed in amygdala tissues from male subjects with Lewy body disorders compared to unaffected male controls, supporting the importance of this chaperone in human disease. Women expressed higher amygdalar Hsp70 levels compared to men, regardless of disease status. Together, these data provide a new link between biological sex and a key chaperone that orchestrates proteostasis.
(© 2021. The American Society for Experimental NeuroTherapeutics, Inc.)
Databáze: MEDLINE
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