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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autophagy / physiology
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Axons / metabolism
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Axons / pathology
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Axons / ultrastructure
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Charcot-Marie-Tooth Disease / genetics
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Charcot-Marie-Tooth Disease / metabolism
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Charcot-Marie-Tooth Disease / physiopathology
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Cytoplasm / genetics
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Cytoplasm / metabolism
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Cytoplasm / pathology
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Disease Models, Animal
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Humans
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Inclusion Bodies / metabolism*
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Inclusion Bodies / pathology
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Inclusion Bodies / ultrastructure
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Lysosomes / metabolism
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Lysosomes / pathology
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Lysosomes / ultrastructure
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Mice
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Mice, Transgenic
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Microscopy, Electron, Transmission
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Myelin Proteins / genetics
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Myelin Proteins / metabolism*
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Nerve Fibers, Myelinated / metabolism*
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Nerve Fibers, Myelinated / pathology
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Nerve Fibers, Myelinated / ultrastructure
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Peripheral Nerves / metabolism*
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Peripheral Nerves / pathology
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Peripheral Nerves / physiopathology
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Peripheral Nervous System Diseases / genetics
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Peripheral Nervous System Diseases / metabolism*
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Peripheral Nervous System Diseases / physiopathology
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Phagosomes / metabolism
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Phagosomes / pathology
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Phagosomes / ultrastructure
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism
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Schwann Cells / metabolism
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Schwann Cells / pathology
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Ubiquitin / genetics
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Ubiquitin / metabolism
Substances
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Myelin Proteins
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PMP22 protein, human
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Ubiquitin
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Proteasome Endopeptidase Complex