Alterations in degradative pathways and protein aggregation in a neuropathy model based on PMP22 overexpression

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.