Molecular mechanisms of proteinopathies across neurodegenerative disease: a review
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(2019) 1:35
Neurological Research and Practice
REVIEW
Open Access
Molecular mechanisms of proteinopathies across neurodegenerative disease: a review Alexander P. Marsh1,2
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
Background Numerous neurodegenerative diseases (ND) share remarkably common pathogenic features in spite of the diversity of clinical symptoms [6, 7]. For many, their pathogenesis is linked by: the misfolding of proteins that aggregate within specific brain regions; significant neuroinflammation and increased oxidative stress of those areas; with final degeneration of neural tissue [7, 48]. However, the molecular mechanisms responsible for the process of this conformational change from proportionate, healthy, functional proteins to pathological, accumulated structures is not yet fully understood [7, 48]. There is new discussion in the literature that the mechanisms behind these pathogenic features of common NDs may be similar, linking these disease processes in a way that was previously thought distinct. This review will focus on the current evidence for the similarities between mechanisms of (1) protein folding and quality control; and (2) protein propagation, specifically with respect to the validity of a shared prion-like propagation hypothesis. In discussion, the inclusion of proteins will be largely limited to those only for which there is the clearest evidence base [49]. Correspondence: [email protected] 1 School of Psychology, Cardiff University, Cardiff, UK 2 School of Psychological Science, University of Bristol, Bristol, UK
Protein folding and quality control In order for the approximately 15,000 proteins present in the neural proteome to fulfil their biological function, they often require folding consistent with exact instructions encoded in the amino-acid sequence [23, 44]. However, the number of potential conformations of even a small polypeptide (around 100 amino acids) is vast, around 1 × 1018 conformations [3]; furthermore their native states often have only marginal stability under normal physiological conditions [23]. It is unsurprising then, the process of protein folding
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