Protein Folding, Aggregation, and Cell Death

The protein homeostasis system, including autophagy, chaperone, and unfolded protein response, is one of the most essential gatekeepers to maintain cell homeostasis. Thus, the loss of protein homeostasis due to protein misfolding and aggregation often results in cell death with gain-of-toxic function and loss-of-function diseases such as neurodegenerative and many other aging-related disorders. Key and fundamental properties of protein (mis)folding and aggregation in causing cell death have been increasing revealed. However, a clearer understanding of the complex mechanisms of protein misfolding diseases remains elusive. This Special Issue focuses on in vitro and in vivo studies of protein folding, aggregation, and cell death.

Dear Colleagues,

Proteins are one of the most fundamental players for numerous biological processes that sustain living organisms. The correct folding of nascent polypeptides from unstructured conformations to the native structure in cells is a prerequisite for gain-of-function of proteins. Stochastic and environment-induced misfolding often results in irreversible protein aggregation, which causes loss-of-function and gain-of-toxic-function of proteins by damaging organelles and inducing cell death.

The protein homeostasis (proteostasis) system, including autophagy, unfolded protein response, and chaperone function, is fundamental to keep cell homeostasis. Among them, chaperone plays a central role for protein homeostasis by helping correct folding and preventing aggregation of misfolded proteins. Most seriously, errors in the proteostasis system in organelles, cells, tissues, and organs give rise to various protein misfolding diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), type 2 diabetes mellitus (T2DM), and amyotrophic lateral sclerosis (ALS). Misfolded and aggregated proteins interact with distinct cellular membranes, e.g., the plasma and organelle membranes, which affects the regulation of organelle function and intracellular signaling associated with apoptotic and non-apoptotic cell death processes. In addition, the interaction of mis-regulated protein aggregates with cellular organelles such as the mitochondria and endoplasmic reticulum has shown the loss of cellular calcium homeostasis with oxidative stress, thereby leading to several types of protein misfolding diseases.

Although several key and underlying aspects of protein folding, misfolding-induced aggregation, chaperone function, and their relation to cell death have been suggested, complicated linkages among these biological and pathological processes remain to be further discussed. In order to gain a deeper understanding, we invite cutting-edge researchers to submit original and review articles on the broad topic of “Protein Folding, Aggregation, and Cell Death”. This Special Issue will collect comprehensive manuscripts and provide valuable insight for the scientific community, ranging from basic to clinical researchers. Original research articles, timely reviews, and short communications are welcome.

Dr. Katsuya Iuchi

Dr. Young-Ho Lee

Dr. Masaki Okumura

Guest Editors

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