Protein misfolding and aggregation in neurodegenerative diseases: a review of pathogeneses, novel detection strategies, and potential therapeutics

Abstract

Protein folding is a complex, multisystem process characterized by heavy molecular and cellular footprints. Chaperone machinery enables proper protein folding and stable conformation. Other pathways concomitant with the protein folding process include transcription, translation, post-translational modifications, degradation through the ubiquitin-proteasome system, and autophagy. As such, the folding process can go awry in several different ways. The pathogenic basis behind most neurodegenerative diseases is that the disruption of protein homeostasis (i.e. proteostasis) at any level will eventually lead to protein misfolding. Misfolded proteins often aggregate and accumulate to trigger neurotoxicity through cellular stress pathways and consequently cause neurodegenerative diseases. The manifestation of a disease is usually dependent on the specific brain region that the neurotoxicity affects. Neurodegenerative diseases are age-associated, and their incidence is expected to rise as humans continue to live longer and pursue a greater life expectancy. We presently review the sequelae of protein misfolding and aggregation, as well as the role of these phenomena in several neurodegenerative diseases including Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, transmissible spongiform encephalopathies, and spinocerebellar ataxia. Strategies for treatment and therapy are also conferred with respect to impairing, inhibiting, or reversing protein misfolding.

FAIM Is a Non-redundant Defender of Cellular Viability in the Face of Heat and Oxidative Stress and Interferes With Accumulation of Stress-Induced Protein Aggregates

“…A key element of cellular homeostasis lies in maintaining proteostasis to avoid accumulation of dysfunctional proteins due to stress-related insults. Protein homeostasis is particularly critical for cells because cells are continuously exposed to cellular stress which causes protein misfolding (Chen et al, 2011;Diaz-Villanueva et al, 2015;Gandhi et al, 2019). Here we report a new mammalian protein, Fas Apoptosis Inhibitory Molecule (FAIM, also termed FAIM1), that protects cells from cellular stress.…”

The Effect of Proline cis-trans Isomerization on the Folding of the C-Terminal SH2 Domain from p85

“…A detailed description of the mechanism by which a polypeptide chain achieves its functionally active conformation is one of the central problems of protein science [1][2][3][4][5][6]. In fact, it is well-established that aberrant folding into non-native misfolded conformations may lead to potentially devastating events that lead to severe human pathologies [7][8][9]. Our current understanding of protein folding is predominantly based on the study of small single-domain proteins, with a specific focus on elucidating the general rules of folding, as well as on identifying the recurring features of misfolded traps [10][11][12][13][14][15][16][17].…”

“…In general, protein misfolding is initiated by the transient accumulation of non-native contacts. These interactions may either spontaneously break, with the protein folding towards its native conformation, or drag the polypeptide chain towards long-lived misfolded conformations that may potentially lead to aggregation [7][8][9]. Because of the links between aggregation and disease, the study of misfolding phenomena is of particular importance and much experimental effort has been devoted to understanding them.…”

Smart Chemiluminescence Probes and Dual-Amplification of Signal for Detection of Amyloid Beta Species in Alzheimer’s Disease Model

“…Although we only performed validations with Ab species, we believe that the strategy for probe designing and CRET method can be extended to other misfolding proteins such as tau, alpha-synucleins, TDP-43, amylin, fibrinogen, prion, fused in sarcoma (FUS) protein, SOD, and transthyretin 42,76 . These proteins probably also meet the designing requirements, which include hydrophobic beta-sheets for binding of specific small molecule probes to turn-on luminescence, and the close proximity of abundant beta-sheets to randomly positioning the paired non-conjugated probes for CRET occurrence.…”