Emerging Role for Autophagy in the Removal of Aggresomes in Schwann Cells

Abstract

The presence of protein aggregates in the nervous system is associated with various pathological conditions, yet their contribution to disease mechanisms is poorly understood. One type of aggregate, the aggresome, accumulates misfolded proteins destined for degradation by the ubiquitin-proteasome pathway. Peripheral myelin protein 22 (PMP22) is a short-lived Schwann cell (SC) protein that forms aggresomes when the proteasome is inhibited or the protein is overexpressed. Duplication, deletion, or point mutations in PMP22 are associated with a host of demyelinating peripheral neuropathies, suggesting that, for normal SC cell function, the levels of PMP22 must be tightly regulated. Therefore, we speculate that mutant, misfolded PMP22 might overload the proteasome and promote aggresome formation. To test this, sciatic nerves of Trembler J (TrJ) neuropathy mice carrying a leucine-to-proline mutation in PMP22 were studied. In TrJ neuropathy nerves, PMP22 has an extended half-life and forms aggresome-like structures that are surrounded by molecular chaperones and lysosomes. On the basis of these characteristics, we hypothesized that PMP22 aggresomes are transitory, linking the proteasomal and lysosomal protein degradation pathways. Here we show that Schwann cells have the ability to eliminate aggresomes by a mechanism that is enhanced when autophagy is activated and is primarily prevented when autophagy is inhibited. This mechanism of aggresome clearance is not unique to peripheral glia, because L fibroblasts were also capable of removing aggresomes. Our results provide evidence for the involvement of the proteasome pathway in TrJ neuropathy and for the role of autophagy in the clearance of aggresomes.

Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast

“…Autophagic response was already reported to be induced by misfolded proteins. 29,30 However, if the Dfmc1 model used here effectively accumulates a-F1 and b-F1 as large matricial aggregates under autophagy-promoting conditions 20,21 (heat stress and anaerobiosis), such aggregates also accumulate in cells grown under aerobiosis (Figure 2d), without induction of autophagy. Hence, protein misfolding is not the 'stressinducing' event of autophagy in our study.…”

“…29,30 Furthermore, in yeast, impairment of the Yme1p-mediated degradation of Cox2p subunits that are not correctly assembled in cytochrome c oxidase complex of the respiratory chain, leads to mitochondrial degradation by a poorly characterised process. 31,32 As already stated, Dfmc1 cells grown at nonpermissive temperature are known to accumulate a-F1 and b-F1 aggregates in the mitochondrial matrix.…”

The pleiotropic role of autophagy: from protein metabolism to bactericide

“…16,17 Inhibition of autophagy induces aggregate formation, whereas rapamycin-induced upregulation of autophagy reduces it. [18][19][20][21] Furthermore, amelioration of neurodegeneration and improvement of behavior were reported in a D. melanogaster Huntington model following treatment with a rapamycin analog, CCI-779. 21 It has been speculated that aggregates can be degraded by autophagy Figure 2 Molecular mechanism of autophagy regulation and autophagosome formation.…”

Protein misfolding and clearance in demyelinating peripheral neuropathies

“…The aggresome-autophagy pathway has emerged as another crucial protein quality control system in Schwann cells that degrades misfolded and aggregated proteins. [14][15][16] Reports by our group and others indicate that Schwann cells handle misfolded PMP22 and SIMPLE by sequestering them into perinuclear aggresomes through a mechanism requiring microtubule-dependent retrograde transport 3,14 ( Fig. 1 and step 8).…”