Deregulated autophagy is an upstream event that directly contributes to caspase-dependent neuronal cell death

摘要

Cupric chloride induces neuronal death by causing abnormal autophagic flux Although genetic mutations of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amy- otrophic lateral sclerosis (ALS) have been identified and studied for their causative role, environmental factors, including heavy metals are also known to be associated with neurodegenerative dis- eases. Heavy metals are necessary to maintain cellular physiology whereas their abnormal accumulation or deficiency result in cell death or dysfunctions. However, it has not been well studied how heavy metals affect neurodegeneration. Therefore, we attempted to probe how heavy metals such as cupric chloride (CuClz) cause neu- ronal cell death and mainly focused on apoptosis and autophagy. In the previous study, we found that CuClz induce ROS to promote neuronal cell death. We show that CuClz induce ROS and Ca?*, ini- tial triggers, which damage cell survival in MN9D dopaminergic neuronal cell line. In our study showed that intracellular free Ca2* is induced lysosomal pH change to promote abnormal autophagic flux, eventually cell death. If blocked the excessive cytosolic Ca2* level to normal levels used BAPTA-AM, one of the Ca2* chelator, abnormal autophagic flux is restored. Thus, CuCl, facilitates cell death by abnormal autophagic flux, depends on Ca?* levels. Taken together, these data indicate that CuClz cause induced abnormal autophagic flux and cell death by elevated cytosolic calcium con- centrations. Furthermore, these phenomena projected in the onset of neurodegenerative diseases that are promoted by sporadic case. In the further study, we will show that change ROS and autophagic flux when treated CuCly, and blocked ROS used ROS scavenger, how to change autophagic flux. It is important to think about environ- mental factors and genetic mutant in neurodegenerative diseases.