title: Biochemical characterization of protein quality control mechanisms during disease progression in the C22 mouse model of CMT1A.
abstract: Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary demyelinating neuropathy linked with duplication of the peripheral myelin protein 22 (PMP22) gene. Transgenic C22 mice, a model of CMT1A, display many features of the human disease, including slowed nerve conduction velocity and demyelination of peripheral nerves. How overproduction of PMP22 leads to compromised myelin and axonal pathology is not fully understood, but likely involves subcellular alterations in protein homoeostatic mechanisms within affected Schwann cells. The subcellular response to abnormally localized PMP22 includes the recruitment of the ubiquitin-proteasome system (UPS), autophagosomes and heat-shock proteins (HSPs). Here we assessed biochemical markers of these protein homoeostatic pathways in nerves from PMP22-overexpressing neuropathic mice between the ages of 2 and 12 months to ascertain their potential contribution to disease progression. In nerves of 3-week-old mice, using endoglycosidases and Western blotting, we found altered processing of the exogenous human PMP22, an abnormality that becomes more prevalent with age. Along with the ongoing accrual of misfolded PMP22, the activity of the proteasome becomes compromised and proteins required for autophagy induction and lysosome biogenesis are up-regulated. Moreover, cytosolic chaperones are consistently elevated in nerves from neuropathic mice, with the most prominent change in HSP70. The gradual alterations in protein homoeostatic response are accompanied by Schwann cell de-differentiation and macrophage infiltration. Together, these results show that while subcellular protein quality control mechanisms respond appropriately to the presence of the overproduced PMP22, with aging they are unable to prevent the accrual of misfolded proteins.
authors.affiliation: *Departments of Neuroscience and Neurology, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL, U.S.A.
authors.forename: Vinita G
authors.initials: VG
authors.lastname: Chittoor
authors.affiliation: *Departments of Neuroscience and Neurology, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL, U.S.A.
authors.forename: Lee
authors.initials: L
authors.lastname: Sooyeon
authors.affiliation: *Departments of Neuroscience and Neurology, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL, U.S.A.
authors.forename: Sunitha
authors.initials: S
authors.lastname: Rangaraju
authors.affiliation: *Departments of Neuroscience and Neurology, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL, U.S.A.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Nicks
authors.affiliation: *Departments of Neuroscience and Neurology, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL, U.S.A.
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Schmidt
authors.affiliation: *Departments of Neuroscience and Neurology, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL, U.S.A.
authors.forename: Irina
authors.initials: I
authors.lastname: Madorsky
authors.affiliation: *Departments of Neuroscience and Neurology, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL, U.S.A.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Narvaez
authors.affiliation: *Departments of Neuroscience and Neurology, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL, U.S.A.
authors.forename: Lucia
authors.initials: L
authors.lastname: Notterpek
mesh_terms: D000367:Age Factors; D000818:Animals; D001343:Autophagy / Q000235:genetics; D039481:CD11b Antigen / Q000378:metabolism; D018833:Chaperonins / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000235:genetics*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009185:Myelin Proteins / Q000235:genetics* / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012583:Schwann Cells / Q000473:pathology; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology
chemical_list: D039481:CD11b Antigen; D018840:HSP70 Heat-Shock Proteins; D009185:Myelin Proteins; C489545:Pmp22 protein, mouse; D011506:Proteins; C018589:lysosomal proteins; D046988:Proteasome Endopeptidase Complex; D018833:Chaperonins