The formation of peripheral myelin protein 22 aggregates is hindered by the enhancement of autophagy and expression of cytoplasmic chaperones
The formation of peripheral myelin protein 22 aggregates is hindered by the enhancement of autophagy and expression of cytoplasmic chaperones
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DOI：
10.1016/j.nbd.2006.09.018
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发表时间：
2007-02-01
影响因子：
6.1
通讯作者：
Notterpek, Lucia
中科院分区：
文献类型：
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作者：
Fortun, Jenny;Verrier, Jonathan D.;Notterpek, Lucia
错误折叠蛋白的积累与各种神经退行性疾病有关。外周髓磷脂蛋白22（PMP 22）是一种遗传性神经病相关的短寿命分子，当蛋白酶体被抑制或蛋白质突变时，它会形成攻击体。我们先前表明，预先存在的PMP 22聚集体的去除是由自噬辅助的。在这里，我们研究了这种聚集体的积累是否可以通过实验诱导自噬和/或分子伴侣来抑制。蛋白酶体抑制过程中自噬的增强阻碍了蛋白质聚集体的形成，并与积累的蛋白酶体底物的减少相关。相反，同时抑制自噬和蛋白酶体增加聚集体的形成。格尔德霉素处理或热休克预处理引起的热休克蛋白水平的增加同样阻碍了攻击体的形成。自噬和分子伴侣在防止错误折叠的PMP 22积累方面的有益作用是累加的，并为与PMP 22突变相关的遗传性神经病的治疗方法提供了潜在的途径。(c)2006年爱思唯尔公司All rights reserved.
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 beat 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. (c) 2006 Elsevier Inc. All rights reserved.