Molecular mechanisms of proteinopathies across neurodegenerative disease: a review

Abstract

Background: Although there is a range of different symptoms across neurodegenerative diseases, they have been noted to have common pathogenic features. An archetypal feature shared between these diseases is protein misfolding; however, the mechanism behind the proteins abnormalities is still under investigation. There is an emerging hypothesis in the literature that the mechanisms that lead to protein misfolding may be shared across neurodegenerative processes, suggesting a common underlying pathology.

Main body: This review discusses the literature to date of the shared features of protein misfolding, failures in proteostasis, and potential propagation pathways across the main neurodegenerative disorders.

Conclusion: The current data suggests, despite overarching processes being shared, that the molecular events implicated in protein pathology are distinct across common neurodegenerative disorders.

Keywords: Neurodegeneration; Protein folding.

Fig. 1

Quality Control of Misfolded Proteins. Green arrows denote chaperone pathways. When a misfolded protein occurs, it can be detected by a molecular chaperone and refolded into a native protein. If this process cannot be completed, either because the native protein is unable to undergo further conformational change or because it has formed an aggregate, it can be sequestered and degraded at a later stage. When protein aggregates form in either an amorphous, fibrillary or oligomeric state, chaperone proteins can initiate two destruction responses. They can target them for destruction via the Ubiquitin-proteasome pathways by facilitating ubiquitin tagging, or facilitate action via BAG3/p62 them for autophagal degradation. ER = Endoplasmic Reticulum; E1 = ubiquitin–activating enzymes; E2 = ubiquitin–conjugating enzymes and E3 = ubiquitin ligases. [Based on Reference Hartl [23] and Tofaris & Buckley [52]]