Aggregation of Disordered Proteins Associated with Neurodegeneration

• Published in: International journal of molecular sciences Vol. 24; no. 4; p. 3380
• Main Authors: Tsoi, Phoebe S, Quan, My Diem, Ferreon, Josephine C, Ferreon, Allan Chris M
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.02.2023; MDPI
• Subjects: Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - chemistry; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Brain; DNA-binding protein; Humans; Intrinsically Disordered Proteins; Mutation; Nervous system diseases; Neurodegeneration; Neurodegenerative Diseases; Oligomerization; Oligomers; Parkinson Disease - metabolism; Parkinson's disease; Protein binding; Protein folding; Proteins; Review; Synuclein; tau; Tau protein; tau Proteins; TDP-43; α-synuclein; LLPS; Aβ; neurodegenerative diseases; liquid–liquid phase separation; AlphaFold; TDP-43; tau; intrinsically disordered proteins; α-synuclein; biomolecular condensates
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24043380

Cellular deposition of protein aggregates, one of the hallmarks of neurodegeneration, disrupts cellular functions and leads to neuronal death. Mutations, posttranslational modifications, and truncations are common molecular underpinnings in the formation of aberrant protein conformations that seed aggregation. The major proteins involved in neurodegeneration include amyloid beta (Aβ) and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and TAR DNA-binding protein (TDP-43) in amyotrophic lateral sclerosis (ALS). These proteins are described as intrinsically disordered and possess enhanced ability to partition into biomolecular condensates. In this review, we discuss the role of protein misfolding and aggregation in neurodegenerative diseases, specifically highlighting implications of changes to the primary/secondary (mutations, posttranslational modifications, and truncations) and the quaternary/supramolecular (oligomerization and condensation) structural landscapes for the four aforementioned proteins. Understanding these aggregation mechanisms provides insights into neurodegenerative diseases and their common underlying molecular pathology.