Abstract:

Neurodegenerative disease is a condition in which subpopulations of neuronal cells of the brain and spinal cord are selectively lost. A common event in many neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis and prion diseases, is the increased level of endoplasmic reticulum (ER) stress caused by accumulation and deposits of inclusion bodies that contain abnormal aggregated proteins. However, the exact contributions to and causal effects of ER stress in neuron degeneration are not clear.
The proper functioning of ER is critical for numerous aspects of cell physiology. Accordingly, the ability to respond to perturbations in ER function, called ER stress, is a fundamentally important property of all cells. ER stress includes the accumulation of unfolded, misfolded or excessive protein, alterations in calcium storage, ER lipid or glycolipid imbalances, or changes in the redox or ionic conditions of the ER lumen. The ER responds to the stressors by activating intracellular signal transduction pathways, collectively called the unfolded protein response (UPR). ER stress can be acute or chronic, chronic ER stress can be persistently tolerated for days to years, as in the case of neurodegenerative diseases, so that, even if some cell death occurs, the majority of cells will ultimately survive and adapt to the stress. Clearly, a better understanding and manipulation of the ER stress level could be beneficial in treating neurodegenerative diseases. In neurons limited ER stress could be tolerated, but still position the cells to be vulnerable to a physiological insult that is sub-lethal.