title: Alterations in degradative pathways and protein aggregation in a neuropathy model based on PMP22 overexpression.
abstract: Charcot-Marie-Tooth disease type 1A (CMT1A) is commonly associated with duplication of the peripheral myelin protein 22 (PMP22) gene. Mice expressing seven copies of the human PMP22, termed C22, suffer from a demyelinating neuropathy and display phenotypic traits of CMT1A. In this article, we investigate whether protein aggregates play a role in the CMT1A-like pathology of C22 mice. Utilizing biochemical and immunochemical tools, we found slowed turnover rate of the newly-synthesized PMP22 and the presence of cytoplasmic protein aggregates in affected nerves. The formation of these aggregates correlates with reduced proteasome activity and the accumulation of detergent-insoluble ubiquitinated substrates. A fraction of the aggregates associates with autophagosomes and lysosomes. Together, these data indicate that as a result of missorting and inefficient proteasomal degradation, the aggregation of PMP22 and recruitment of autophagosomes and lysosomes are key factors in the subcellular pathogenesis of CMT1A neuropathies.
authors.affiliation: Department of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Fortun
authors.forename: Jocelyn C
authors.initials: JC
authors.lastname: Go
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Amici
authors.forename: William A
authors.initials: WA
authors.lastname: Dunn
authors.forename: Lucia
authors.initials: L
authors.lastname: Notterpek
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D001369:Axons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D010525:Peripheral Nerves / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010588:Phagosomes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
chemical_list: D009185:Myelin Proteins; C073687:PMP22 protein, human; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex