Biochemical Characterization of Protein Quality Control Mechanisms during Disease Progression in the C22 Mouse Model of CMT1A

Autor: Irina Madorsky, Lee Sooyeon, Jordan T. Schmidt, Jessica Nicks, Lucia Notterpek, Vinita G. Chittoor, Sunitha Rangaraju, Diana C. Narvaez
Jazyk: angličtina
Rok vydání: 2013
Předmět:
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
Zdroj: ASN Neuro, Vol 5 (2013)
ASN NEURO
ISSN: 1759-9091
1759-0914
Popis: 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.
Databáze: OpenAIRE
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