CMT 1A: Alterations in degradative pathways and protein aggregation in a neuropa

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Neurobiol Dis. 2005 Nov 30

Alterations in degradative pathways and protein aggregation in a

neuropathy model based on PMP22 overexpression.

Fortun J, Go JC, Li J, Amici SA, Dunn WA Jr, Notterpek L.

Departments of Neuroscience and Anatomy and Cell Biology, College of

Medicine, McKnight Brain Institute, University of Florida,

Gainesville, FL 32610, USA.

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.