Myelin under stress

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J Neurosci Res. 2009 Mar 27.

Myelin under stress.

D' M, Feltri ML, Wrabetz L.

San Raffaele Scientific Institute, DIBIT, Milan, Italy.

The capacity to fold proteins properly is fundamental for cell survival.

Secreted and transmembrane proteins are synthesized in the endoplasmic reticulum

(ER), an organelle that has the ability to discriminate between native and

nonnative proteins, in a process called protein quality control.

When folding is not properly achieved, misfolded proteins can accumulate. The

terminally misfolded proteins are typically retrotranslocated into the cytoplasm

for degradation by the proteasome, in a process known as endoplasmic

reticulum-associated degradation.

However, if the degradation is insufficient, accumulation of abnormal proteins

in the ER activates the unfolded protein response (UPR), a complex set of new

signals aimed to reduce further the load of abnormal protein in the ER. Massive

synthesis of myelin lipids and proteins is necessary to support myelinogenesis.

Not surprisingly, therefore, ER stress (including the UPR), the proteasome, and

autophagy (lysosomes) have been implicated in myelin disorders, such as

Pelizaeus-Merzbacher disease and vanishing white matter disease in the central

nervous system and Charcot-Marie-Tooth neuropathies in the peripheral nervous

system.

Here we discuss recent evidence supporting an important role for ER stress in

myelin disorders.