The formation of peripheral myelin protein 22 aggregates is hindered by the enhancement of autophagy and expression of cytoplasmic chaperones

Abstract

The accumulation of misfolded proteins is associated with various neurodegenerative conditions. Peripheral myelin protein 22 (PMP22) is a hereditary neuropathy-linked, short-lived molecule that forms aggresomes when the proteasome is inhibited or the protein is mutated. We previously showed that the removal of pre-existing PMP22 aggregates is assisted by autophagy. Here we examined whether the accumulation of such aggregates could be suppressed by experimental induction of autophagy and/or chaperones. Enhancement of autophagy during proteasome inhibition hinders protein aggregate formation and correlates with a reduction in accumulated proteasome substrates. Conversely, simultaneous inhibition of autophagy and the proteasome augments the formation of aggregates. An increase of heat shock protein levels by geldanamycin treatment or heat shock preconditioning similarly hampers aggresome formation. The beneficial effects of autophagy and chaperones in preventing the accumulation of misfolded PMP22 are additive and provide a potential avenue for therapeutic approaches in hereditary neuropathies linked to PMP22 mutations.

Protein misfolding and clearance in demyelinating peripheral neuropathies

“…Although the signaling events that target misfolded PMP22 and SIMPLE into aggresomes have not been identified, our previous finding 17 of parkin-mediated K63 linked poly-ubiquitination in targeting misfolded protein to aggresomes via interactions with the dynein adaptor protein HDAC6 suggest that as yet-to-be identified E3 ligases and adaptor proteins could be responsible for targeting misfolded PMP22 and SIMPLE to aggresomes. Moreover, we 3 and others 18 showed that PMP22-and SIMPLE-positive aggresomes are tightly surrounded by autophagosome markers (Fig. 1 and step 9) and degraded by autophagy ( Fig.…”

Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice

“…Autophagy, stimulated via fasting or rapamycin, or an increase in the heat shock response, can improve the phenotype of some PMP22-related neuropathies (Fortun et al, 2007;Rangaraju et al, 2008Rangaraju et al, , 2010Madorsky et al, 2009), and salubrinal enhancement of the integrated stress response (ISR) ameliorated hypomyelination and oligodendrocyte loss in cultured hippocampal slices exposed to IFN- (Lin et al, 2008).…”

The Schwann Cell-Axon Link in Normal Condition or Neuro-Degenerative Diseases: An Immunocytochemical Approach

“…The proteasome is a multi-catalytic complex involved in a variety of cellular processes, including the degradation of short-lived proteins (Goldberg, 2003). PMP-22 is a short-live molecule, that form aggregates when the proteasome is inhibited or the protein is mutated (Fortun et al, 2007). It is conceivable that the amount of PMP-22 targeted for degradation is increased in the gene duplication and point mutations disease, which could overwhelm the proteasome and lead to the accumulation of miss-folded proteins along the secretory pathway.…”