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Licensed Unlicensed Requires Authentication Published by De Gruyter February 12, 2019

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

  • Jason Gandhi , Anthony C. Antonelli , Adil Afridi , Sohrab Vatsia , Gunjan Joshi , Victor Romanov , Ian V.J. Murray and Sardar Ali Khan EMAIL logo

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.

Acknowledgments

The authors are thankful to Drs. Kelly Warren, Inefta Reid, Todd Miller, and Peter Brink for departmental support, as well as to Mrs. Wendy Isser and Ms. Grace Garey for literature retrieval.

  1. Conflict of interest statement: The authors have no conflicts of interest to declare.

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Received: 2018-05-25
Accepted: 2018-08-03
Published Online: 2019-02-12
Published in Print: 2019-05-27

©2019 Walter de Gruyter GmbH, Berlin/Boston

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