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

Protein misfolding and clearance in demyelinating peripheral neuropathies

“…Recent studies by our laboratory and others have provided important insights into the molecular and cellular pathways involved in demyelinating CMT, which may help develop better treatments for this disease. [6][7][8] and MPZ. 9,10 How misfolding of these membrane proteins with different topologies contributes to demyelinating neuropathy remain unknown.…”

Identification of the Drosophila Ortholog of HSPB8

“…Moreover, aggregation of mutated proteins is also commonly observed in several types of neuromuscular and muscular disorders (e.g. Charcot-Marie-Tooth type 1A, desmin-related myopathy, and muscular dystrophy), thus further underscoring a causal role for protein misfolding in neuronal and muscular cell degeneration (3)(4)(5)(6). Hence, suppression of protein aggregation and acceleration of protein removal are considered to be common therapeutic approaches to treat the protein conformational disorders (7,8).…”

“…Hence, suppression of protein aggregation and acceleration of protein removal are considered to be common therapeutic approaches to treat the protein conformational disorders (7,8). Both suppression of protein aggregation and degradation of misfolded proteins can be achieved through stimulation of the protein quality control system, which includes molecular chaperones of the heat shock protein (HSP) 3 families and degradation systems (proteasome, chaperone-mediated autophagy, and macroautophagy) (8). It has been shown that up-regulation of molecular chaperones and stimulation of autophagy can protect from the toxic effects of aggregating proteins both in cellular and animal (e.g.…”

“…For Charcot-Marie-Tooth disease type 1, which is characterized by the aggregation of mutated peripheral myelin protein 22 (PMP22), a progressive impairment of the proteasome function was found (25)(26)(27). Interestingly, mutated PMP22 is mainly targeted to autophagy for degradation (3,28). As such, these data point to imbalanced protein homeostasis as a possible general event implicated in the pathogenesis and/or progression of neurodegenerative and neuromuscular disorders.…”

Experimental Therapeutics in Hereditary Neuropathies: The Past, the Present, and the Future

“…3 An alternative approach for CMT1A, which requires preclinical testing, would be one that targets PMP22 aggregates, on the hypothesis that the aggregates cause proteosomal impairment and SC toxicity. 3,14 Trophic factor deficits (e.g., ciliary neurotrophic factor) have been found in rodent models and CMT1A nerves, suggesting that trophic factor replacement may be efficacious. 16 Animal models of CMT1A suggest that inflammatory responses influence demyelination.…”