Resumen de Mitophagy dysfunction in peripheral and neural models of alzheimer disease
Alzheimer disease (AD) is a neurodegenerative disorder characterized by the accumulation of Aβ peptide and hyperphosphorylated Tau protein. Mitochondrial dysfunction and oxidative damage have been previously reported not only in the vulnerable regions of affected brain but also in peripheral cells in the disease. Autophagy has been demonstrated to play a fundamental role in AD related proteinopathy. Moreover, anomalies at different levels of autophagy pathway have been described suggesting that autophagy failure might be considered an early event of the disease. Therefore, the aim of this work was the study of autophagy pathway besides mitochondrial recycling process in human cellular models of both familial and sporadic types of AD.
The overexpression of APP in human fibroblasts demonstrated an activation of autophagy flux due to an enhanced degradation phase correlating with higher lysosomal activity. Increased mitochondrial content revealed a defect in mitophagy due to defective labeling of damaged mitochondria by PARK2. The addition of Tau to APP overexpression model aggravated the mitophagy dysfunction leading to unachievable recovery of mitochondrial membrane potential after an insult that resulted in the further accumulation of dysfunctional mitochondria labeled by PINK1.
The study of fibroblasts derived from familial AD patients associated to presenilin mutation revealed a deregulation of autophagy degradation phase correlating with lysosome acidification deficiency leading to accumulation of autophagic vesicles. This resulted in a mitochondrial recycling failure that caused the accumulation of mitochondria and PARK2. Worsened mitophagy dysfunction was observed in neurons derived from induced pluripotent stem cells harboring the same presenilin mutation triggering increased accumulation of mitochondria, PARK2 and PINK1.
Fibroblasts derived from sporadic AD patients demonstrated compromised mitochondrial dynamics and function as well as deficient autophagy induction and lysosomal anomalies resulting in the accumulation of oxidized and ubiquitinated proteins. Mitophagy impairment has been proven in these cells due to diminished PARK2 recruitment that caused the accumulation of depolarized mitochondria and PINK1. Patients’ hippocampal samples at early stages of the disease exhibited similar mitophagy alterations showing abnormally increased mitochondrial content together with accumulation of PINK1.
Overexpression of PARK2 in sporadic AD fibroblasts diminished ubiquitinated proteins accumulation, improved its targeting to mitochondria and potentiated autophagic vesicle synthesis allowing the reversion of mitophagy failure. This suggests that autophagy enhancement is a powerful therapeutic strategy.
Our findings indicate that, although there are differences in the deregulation pattern of the mitochondrial recycling process in sporadic and familial AD models, both converge in the same mitophagy failure that causes the accumulation of dysfunctional mitochondria.
