Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases

Abstract

Proteostasis or protein homeostasis is the dynamic regulation of cellular protein to maintain the functional proteome of a cell. Proteostasis is regulated by a complex machinery regulating biogenesis, folding, trafficking, and degradation of proteins. Misfolded and damaged proteins are either degraded by ubiquitin-proteasome systems (UPS) or by autophagy. Dysregulation of proteostasis in the brain and central nervous system (CNS) can induce glial cells to produce inflammatory molecules, affecting proteostasis and thereby leading to neuroinflammation. Abnormalities in proteostasis and inflammation are key pathophysiological components of normal aging as well as neurodegenerative disorders (NDDs). Since neurons have a limited capacity for regeneration, proteostasis plays an essential role in maintaining cellular processes within the central nervous system. Therefore, an interplay between proteostasis and inflammation in the onset and progression of neurodegenerative diseases has emerged as a critical area of investigation. This chapter explores the intricate relationship between these two processes and their collective impact on the central nervous system. Furthermore, we provide a comprehensive review of how disruptions in proteostasis, leading to the accumulation of misfolded or aggregated proteins, can trigger an inflammatory response or, conversely, result in neuronal dysfunction. In addition, this chapter highlights the bidirectional relationship between inflammation and dysregulated proteostasis and how it may contribute to the clinical manifestations of various neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). © 2025 The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.