Neurons, when faced with endogenous and exogenous insults, mobilize their network of machinery to relief stress. Failure of this attempt often results in neuronal death. Many human neurological diseases such as Alzheimer's and Parkinson's diseases are characterized by the pathological loss of neurons. The long-term objective of our research is to understand how neurons respond to stress and the role of dysfunction of survival response in neurodegenerative process. We propose in this application to study a novel link between endoplasmic reticulum (ER) and lysosomes, two key organelles responsible for handling stress and maintaining cellular homeostasis, in neuronal stress response and in neurodegenerative process. Studies indicate that many toxic signals perturb ER homeostasis. Correcting ER stress requires the activation of multiple ER signal pathways. However, prolonged stress may also direct ER to generate cell death signals. There is strong evidence to implicate the dysfunction of ER stress response in both acute and chronic neurological diseases. Lysosomes participate in maintaining neuronal homeostasis by degrading intracellular constitutes in response to stress, a process named autophagy. Chaperone-mediated autophagy (CMA) is distinct from the traditional macroautophagy in that CMA selectively degrades individual proteins. CMA is critical since nearly 30% of cytosolic proteins contain the conserved motif recognized by CMA and are potential regulatory targets. Recent studies suggest that dysfunction of CMA plays an important role in neuronal stress and neurological diseases. Despite their respective roles in handling neuronal stress, it is not known whether ER stress and CMA are linked. Our recent studies showed that the nonfunctional form of neuronal survival protein, myocyte enhancer factor 2D (MEF2D), is degraded by CMA and disruption of this regulatory process underlies neuronal stress and occurs in models of Parkinson's diseases. Our preliminary studies indicate that ER stress leads to MEF2D degradation, which is dependent on CMA and requires p38 MAPK, a well-known stress sensor. Together, these intriguing data support an exciting hypothesis that ER stress activates CMA via a p38 dependent mechanism. We will combine molecular and cellular methods and use in vivo and genetic models to determine in Aim I, the role of p38 MAPK in ER stress-mediated activation of CMA in neurons;
in Aim II, the mechanisms by which p38 senses ER stress and activates CMA;and in Aim III, the role of ER stress-p38-CMA pathway in neuronal viability. This study will establish a novel link between two key processes, ER stress and lysosomal CMA, reveal the stress sensor p38 MAPK as the mediator, uncover the molecular mechanism(s) underlying this regulatory pathway, and establish a functional role for this network in neuronal stress and survival. This new mechanistic network should be highly relevant to the pathogenic process of neurological diseases and may aid the development of novel therapeutic strategies.
Neurological disorders including chronic Alzheimer's and Parkinson's diseases and acute injuries such as stroke are devastating and currently without effective therapies. The specific causes for many them are not entirely clear but involve loss of specific populations of neurons. Our study will reveal how two critical subcellula organelles and processes responsible for handling neuronal stress and maintaining cellular homeostasis may form a stress response network and study the molecular basis for this critical link. Knowledge gained through this study may help design new therapeutic approaches to treat neurodegenerative diseases and acute injuries.
|Li, Wenming; Zhu, Jinqiu; Dou, Juan et al. (2017) Phosphorylation of LAMP2A by p38 MAPK couples ER stress to chaperone-mediated autophagy. Nat Commun 8:1763|
|Liu, Xiaolei; Huang, Sihua; Wang, Xingqin et al. (2015) Chaperone-mediated autophagy and neurodegeneration: connections, mechanisms, and therapeutic implications. Neurosci Bull 31:407-15|
|Yang, Qian; Li, Wenming; She, Hua et al. (2015) Stress induces p38 MAPK-mediated phosphorylation and inhibition of Drosha-dependent cell survival. Mol Cell 57:721-34|
|Gao, Li; She, Hua; Li, Wenming et al. (2014) Oxidation of survival factor MEF2D in neuronal death and Parkinson's disease. Antioxid Redox Signal 20:2936-48|