Aggregation of Disordered Proteins Associated with Neurodegeneration

Abstract

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.

Keywords: AlphaFold; Aβ; LLPS; TDP-43; biomolecular condensates; intrinsically disordered proteins; liquid–liquid phase separation; neurodegenerative diseases; tau; α-synuclein.

Figure 1

Predicted structure and disorder of Aβ, tau, α-syn, and TDP-43. Structures were predicted using AlphaFold [26], and calculations for disorder were determined using IUPRED2 [27,28,29,30]. IUPRED2 provides IUPred and ANCHOR scores for disordered proteins. ANCHOR predicts disorder based on amino acid sequence, identifying potential binding sites that are disordered in isolation, while IUPred predicts disorder based on energy estimation. IUPred scores from 0 to 0.5 are considered ordered while scores from 0.5 to 1 are considered disordered. Aβ-42 (human) was chosen as the representative peptide for Aβ. Tau (human, UniProt ID: P10636) is highly disordered with a C-terminal helical region. α-Syn (human, UniProt ID: P37840) has a disordered C-terminus and α-helical N-terminus. TDP-43 (human, UniProt ID: Q13148) contains a long unstructured C-terminus. (Note that these are predicted structures only and may not represent the major physiological protein conformations. For example, α-syn has been shown to adopt more random coil-like structures in physiological buffer conditions, with the elongated helical structure predicted using AlphaFold only favored in the presence of ligands such as membrane vesicles [31,32,33]).

Figure 2

Molecular underpinnings of ND-linked IDP misfolding and aggregation.