1. Biochemical Characterization of Protein Quality Control Mechanisms during Disease Progression in the C22 Mouse Model of CMT1A
- Author
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Irina Madorsky, Lee Sooyeon, Jordan T. Schmidt, Jessica Nicks, Lucia Notterpek, Vinita G. Chittoor, Sunitha Rangaraju, and Diana C. Narvaez
- Subjects
Wt, wild-type ,Chaperonins ,LAMP1, lysosomal membrane-associated protein 1 ,pUb, polyubiquitinated ,CathD, Cathepsin D ,Hsp, heat-shock protein ,Mice ,Myelin ,0302 clinical medicine ,Egr2, early growth response 2 ,Charcot-Marie-Tooth Disease ,Peripheral myelin protein 22 ,chaperone ,TFEB, transcription factor EB ,PNGaseF, N-glycosidase F ,0303 health sciences ,CD11b Antigen ,biology ,General Neuroscience ,Age Factors ,HRP, horseradish peroxidase ,CMT1A, Charcot–Marie–Tooth disease type 1A ,Sciatic Nerve ,3. Good health ,Cell biology ,myelin ,medicine.anatomical_structure ,Neutrophil Infiltration ,Disease Progression ,Myelin Proteins ,Research Article ,Proteasome Endopeptidase Complex ,autophagy ,UPS, ubiquitin–proteasome system ,Transgene ,MCP-1, monocyte chemoattractant protein 1 ,Schwann cell ,Mice, Transgenic ,S3 ,endoH, endoglycosidase H ,protein aggregation ,MS, multiple sclerosis ,lcsh:RC321-571 ,ER, endoplasmic reticulum ,03 medical and health sciences ,Oct6, octamer-binding transcription factor 6 ,Lysosome ,ubiquitin ,medicine ,Animals ,Humans ,HSP70 Heat-Shock Proteins ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,030304 developmental biology ,AMC, amino-methyl coumarin ,Macrophages ,Autophagy ,PMP22, peripheral myelin protein 22 ,Proteins ,HSF1, heat-shock factor 1 ,di-8-ANEPPS, 4-[2-(6-dibutylamino)-2-naphthalenyl)ethenyl]-1-(3-sulfopropyl) hydroxide ,LC3, light chain 3 ,Mice, Inbred C57BL ,Disease Models, Animal ,Gene Expression Regulation ,Proteasome ,Chaperone (protein) ,Immunology ,biology.protein ,Schwann Cells ,Neurology (clinical) ,IgG, immunoglobulin ,030217 neurology & neurosurgery - 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., In peripheral nerves of neuropathic C22 mice the frequency of cytosolic PMP22 aggregates increases with age, which elicits a response from protein quality control mechanisms. The combined effects of aging and neuropathic genotype exacerbate disease progression leading to nerve defects.
- Published
- 2013