Neurodegenerative diseases (NDs) are increasingly prevalent, and approximately a quarter of the US population will suffer from a ND during their life. One such ND is amyotrophic lateral sclerosis (ALS), a fatal disease caused by loss of motor neurons (MNs);at present, approximately 30,000 Americans suffer from this disease. Encouragingly, genetic mutations that cause some forms of familial ALS have been identified;however, no effective treatments for ALS exist. As there is evidence that MNs activate the BAX/BAK-dependent apoptosis pathway during ALS, we tested whether loss of Bax and Bak would be beneficial in a mouse model of ALS. Indeed, deletion of Bax and Bak in neurons slows the loss of motor neurons and delays axon degeneration. Furthermore, it delays the onset of paralysis and weight loss and, excitingly, extends survival. However, as BAX and BAK are difficult to target, identification of their upstream activators in MNs in the context of ALS will e essential in developing new therapies for ALS;one such pathway is the unfolded protein response (UPR). The UPR is triggered when unfolded or misfolded proteins accumulate in the endoplasmic reticulum (ER) of a cell, causing "ER stress." When this occurs, the UPR first attempts to restore ER homeostasis by slowing translation and upregulating genes that increase the ER's protein folding capacity. However, if the stress is too severe, the UPR will trigger apoptosis via activation of BAX and BAK. Importantly, there is accumulating evidence that ER stress-induced toxicity is important in driving MN loss in ALS. We have recently discovered that IRE1?, an important UPR effector, is vital in determining whether the UPR signals survival or apoptosis, and we have created chemical-genetic tools that allow us to control IRE1?'s signaling in both cell lines and live mice. Based on our findings, we propose to determine how IRE1? signals BAX/BAK-dependent apoptosis in MNs and whether inhibition of IRE1?'s apoptotic arm is beneficial in ALS. In parallel, appropriate coursework in neuroscience and microscopy will be taken to ensure robust background knowledge necessary to perform the proposed research.
At present, there are roughly 30,000 Americans diagnosed with amyotrophic lateral sclerosis (ALS), a disease that results in paralysis due to the loss the nerves that control voluntary muscle movement, and patients with ALS generally die within 3-5 years of diagnosis. There is strong evidence that in ALS, these nerve cells die because toxic proteins accumulate within the cells. We propose to investigate how cells respond to toxic proteins as a way to prevent activation of cell death;if successful, our research may lead to new therapies for ALS.
|Ghosh, Rajarshi; Wang, Likun; Wang, Eric S et al. (2014) Allosteric inhibition of the IRE1? RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158:534-48|