内质网应激通过STIM2自噬降解介导神经元树突退化的分子机制

Abstract

Endoplasmic reticulum (ER) stress has been highlighted as one of the factors involved in axon/dendrite degeneration, which is an early event in Alzheimer's, Parkinson's diseases as well as in acute disorders such as ischemia and axotomy-induced retinal ganglion cell degeneration. These lines of evidence suggest critical roles of ER stress at the early stage of neurodegeneration, but the relevant mechanism is rarely exploited. In this study, we report that treatment with sublethal level of ER stressors, tunicamycin or brefeldin A, in primary rat neuronal cultures, significantly reduced dendrite arbor. Under the same treatment, either stressor reduced store-operated calcium entry (SOCE) and cytosolic calcium, [Ca 2+ ] i , which were associated with autophagic degradation of stromal interaction molecule 2 (STIM2). Knockdown of ATG7 or activating transcription factor 4 completely reversed the reduction of STIM2 and significantly reversed the inhibition of SOCE under ER stress. Overexpression of STIM2 in neurons significantly prevented the ER stress-induced disruption of dendrite arbor. Altogether, our data reveal an unprecedented mechanism by which ER stress induces dendrite degeneration, that is, ER stress induces autophagic degradation of STIM2, leading to ensued SOCE inhibition and reduced [Ca 2+ ] i , resulting in trimming effect on dendrites.