Proteins are synthesized by decoding the information in mRNAs, which is accomplished by the ribosome. For proteins to function, they first have to fold into their own shapes. However, newly synthesized proteins are prone to misfolding or aggregation in the crowded milieu of cells. Therefore, cells have evolved a wide array of chaperones to help proteins fold. When the folding process fails, the ubiquitin-proteasome system degrades misfolded proteins that are soluble, whereas aggregates of misfolded proteins are mostly cleared by autophagy. These protein quality control pathways are crucial to maintaining protein homeostasis. We are interested in the mechanism whereby cells recognize misfolded proteins.

During aging, misfolded proteins accumulate to form aggregates. These protein aggregates cause various diseases, especially neurodegenerative diseases. For instance, Alzheimer’s disease and Parkinson’s disease are caused by Aβ/Tau aggregates and α-synuclein aggregates, respectively. Despite intensive studies, the mechanism of protein aggregate toxicity still remains elusive. We are trying to understand how protein aggregates result in neurodegenerative diseases that are devastating in this era of aging population.

We are particularly interested in stalled nascent polypeptides. For various reasons, translating ribosomes can stall on mRNAs and proteins being synthesized on such ribosomes are targeted by RQC (ribosome-associated quality control) complex for the subsequent degradation by proteasomes. Ltn1 is an E3 ligase component of the RQC complex that functions to polyubiquitylate stalled nascent polypeptides. Interestingly, LTN1 mutation leads to the formation of detergent-insoluble stalled protein aggregates that may be toxic to cells. Consistently, LTN1 mutant mice exhibit a symptom of the neurodegenerative disorder. We are studying toxic effects of stalled protein aggregates.