title: The formation of peripheral myelin protein 22 aggregates is hindered by the enhancement of autophagy and expression of cytoplasmic chaperones.
abstract: The accumulation of misfolded proteins is associated with various neurodegenerative conditions. Peripheral myelin protein 22 (PMP22) is a hereditary neuropathy-linked, short-lived molecule that forms aggresomes when the proteasome is inhibited or the protein is mutated. We previously showed that the removal of pre-existing PMP22 aggregates is assisted by autophagy. Here we examined whether the accumulation of such aggregates could be suppressed by experimental induction of autophagy and/or chaperones. Enhancement of autophagy during proteasome inhibition hinders protein aggregate formation and correlates with a reduction in accumulated proteasome substrates. Conversely, simultaneous inhibition of autophagy and the proteasome augments the formation of aggregates. An increase of heat shock protein levels by geldanamycin treatment or heat shock preconditioning similarly hampers aggresome formation. The beneficial effects of autophagy and chaperones in preventing the accumulation of misfolded PMP22 are additive and provide a potential avenue for therapeutic approaches in hereditary neuropathies linked to PMP22 mutations.
authors.affiliation: Department of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, 100 Newell Drive, Box 100244, Gainesville, FL 32610-0244, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Fortun
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Verrier
authors.forename: Jocelyn C
authors.initials: JC
authors.lastname: Go
authors.forename: Irina
authors.initials: I
authors.lastname: Madorsky
authors.forename: William A
authors.initials: WA
authors.lastname: Dunn
authors.forename: Lucia
authors.initials: L
authors.lastname: Notterpek
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy / Q000502:physiology; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D006360:Heat-Shock Proteins / Q000378:metabolism; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002479:Inclusion Bodies / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008818:Mice, Neurologic Mutants; D046529:Microscopy, Electron, Transmission; D018832:Molecular Chaperones / Q000378:metabolism*; D009185:Myelin Proteins / Q000378:metabolism*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000473:pathology; D010525:Peripheral Nerves / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D051381:Rats
chemical_list: D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009185:Myelin Proteins; C489545:Pmp22 protein, mouse; D046988:Proteasome Endopeptidase Complex