线粒体UPR基因激活家族性和散发性阿尔茨海默病的证据

Title:Evidence for Mitochondrial UPR Gene Activation in Familial and Sporadic Alzheimer’s Disease

Volume: 13 Issue: 6

Author(s): John S. Beck, Elliott J. Mufson, Scott E. Counts

Affiliation:

关键词: 阿尔茨海默病，线粒体，线粒体自噬，早老素，未折叠蛋白反应

摘要: Mitochondrial perturbations such as oxidative stress, increased fission/fusion dysfunction, and mitophagy are consistent features of Alzheimer’s disease (AD), yet the mechanisms that initiate these perturbations are unclear. One potential source for mitochondrial defects could be an imbalance in mitochondrial proteostasis. In this regard, studies indicate that a specialized mitochondrial unfolded protein response (mtUPR) is activated upon the aberrant accumulation of damaged or unfolded proteins in the mitochondrial matrix, resulting in the up-regulation of key genes involved in mitochondrial stabilization. To test whether mtUPR activation occurs in AD, we performed real-time quantitative PCR on postmortem frontal cortex samples from subjects classified as sporadic AD, familial AD linked to presenilin-1 mutations, or cognitively intact controls. Compared to controls, sporadic AD subjects exhibited a significant ~40-60% increase in expression levels of select genes activated by the mtUPR, including mitochondrial chaperones dnaja3, hspd1, and hspe1, mitochondrial proteases clpp and yme1l1, and txn2, a mitochondrial-specific oxidoreductase. Furthermore, levels of all six mtUPR genes were significantly up-regulated by ~70-90% in familial AD compared to controls, and these expression levels were significantly higher compared to sporadic AD. The increase in hspd1 (Hsp60) was validated by western blotting. These data support the concept that both sporadic and familial AD are characterized by mtUPR gene activation. Understanding the physiological consequences of this response may provide subcellular mechanistic clues to selective neuronal vulnerability or endogenous compensatory mechanisms during the progression of AD.

Cite this article as:

John S. Beck, Elliott J. Mufson, Scott E. Counts , Evidence for Mitochondrial UPR Gene Activation in Familial and Sporadic Alzheimer’s Disease, Current Alzheimer Research 2016; 13 (6) . https://dx.doi.org/10.2174/1567205013666151221145445