Protein aggregation and its affecting mechanisms in neurodegenerative diseases

Abstract

Protein aggregation serves as a critical pathological marker in a spectrum of neurodegenerative diseases (NDs), including the formation of amyloid β (Aβ) and Tau neurofibrillary tangles in Alzheimer's disease, as well as α-Synuclein (α-Syn) aggregates in Parkinson's disease, Parkinson's disease-related dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). A significant proportion of patients with amyotrophic lateral sclerosis (ALS) exhibit TDP-43 aggregates. Moreover, a confluence of brain protein pathologies, such as Aβ, Tau, α-Syn, and TDP-43, has been identified in individual NDs cases, highlighting the intricate interplay among these proteins that is garnering heightened scrutiny. Importantly, protein aggregation is modulated by an array of factors, with burgeoning evidence suggesting that it frequently results from perturbations in protein homeostasis, influenced by the cellular membrane milieu, metal ion concentrations, post-translational modifications, and genetic mutations. This review delves into the pathological underpinnings of protein aggregation across various NDs and elucidates the intercommunication among disparate proteins within the same disease context. Additionally, we examine the pathogenic mechanisms by which diverse factors impinge upon protein aggregation, offering fresh perspectives for the future therapeutic intervention of NDs.