Neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis, Alzheimer’s disease, and Parkinson’s disease, are devastating lethal diseases that affect a large number of individuals in the aging population worldwide. The pathological accumulation of specific proteins with aberrant conformation plays a crucial role in driving the progressive dysfunction of specific neurons in selective brain regions in these diseases. The failure of protein quality control and degradation systems, that usually are concomitant with aging, are largely responsible for promoting the pathological deposition of these diseases-causing proteins. Zhang’s research group aims to elucidate the cellular mechanisms involved in the degradation of detrimental misfolded proteins. Our research will contribute significantly to the understanding of the age-onset decline of proteostasis and thus help to combat neurodegenerative diseases and aging.

1. Understanding the mechanistic basis of misfolded protein degradation and deposition pathway.

The eukaryotic ER maintains protein homeostasis by eliminating unwanted proteins by the ER-associated degradation (ERAD) pathway. Despite advances in past decades, many fundamental questions remain to be answered. Zhang’s research will be focused on several aspects of aberrant protein degradation that range from mechanistic studies in vitro to analysis of its importance in cells and animals. The long-term goal of our lab is to understand the principles that govern the clearance and deposition of misfolding-prone proteins, and to identify strategies that could reduce the burden of damaged proteins for cells and organisms.

2. Identifying unknown components that regulate cellular protein homeostasis under pathophysiological conditions.

To date, protein degradation is often examined using artificial substrates or disease relevant mutant proteins. Due to the presence of limited number of endogenous substrates, the importance of protein destruction under physiological conditions has been poorly understood. By using multiple genomic, biochemical, and proteomic strategies, Zhang’s research group is currently investigating ER protein abundance at various conditions in cells (e.g., with elevated or decreased protein degradation capacity). This will lead to discovery of new protein components (e.g., those prone to be misfolded and degraded) that could be involved in ageing, and thus will uncover the interplay of protein degradation and other cellular pathways.

3. Mechanism underlying ER stress response and neurodegenerative diseases.

Unfolded protein response (UPR) is a key quality control system that senses ER stress signals and initiates global changes in transcription and translation to maintain ER homeostasis. It is now evident that UPR functions in various physiological conditions, and are master regulators of human disorders including diabetes, cancer, aging, and neurodegeneration. However, little is known about how UPR is modulated under various physiological conditions, such as increased protein synthesis, elevated levels of lipids, and high or low hexosamine levels. Zhang’s lab is performing a genome wide screen for components that are involved in the Ire1-, PERK-, andATF6-UPR branches in mammalian cells. These studies will identify novel factors that are involved in the ER stress response in mammalian cells, and will provide promising therapeutic targets for the treatment of human diseases, such as diabetes, cancer and aging.