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Cell Mol Life Sci. 2018 Sep;75(17):3159-3180. doi: 10.1007/s00018-018-2854-4. Epub 2018 Jun 12.

Mechanisms of protein toxicity in neurodegenerative diseases.

Author information

1
Department of Brain and Cognitive Sciences, DGIST, Daegu, 42988, Republic of Korea.
2
Department of Brain and Cognitive Sciences, DGIST, Daegu, 42988, Republic of Korea. hyosang22@dgist.ac.kr.
3
Department of Brain and Cognitive Sciences, DGIST, Daegu, 42988, Republic of Korea. sblee@dgist.ac.kr.

Abstract

Protein toxicity can be defined as all the pathological changes that ensue from accumulation, mis-localization, and/or multimerization of disease-specific proteins. Most neurodegenerative diseases manifest protein toxicity as one of their key pathogenic mechanisms, the details of which remain unclear. By systematically deconstructing the nature of toxic proteins, we aim to elucidate and illuminate some of the key mechanisms of protein toxicity from which therapeutic insights may be drawn. In this review, we focus specifically on protein toxicity from the point of view of various cellular compartments such as the nucleus and the mitochondria. We also discuss the cell-to-cell propagation of toxic disease proteins that complicates the mechanistic understanding of the disease progression as well as the spatiotemporal point at which to therapeutically intervene. Finally, we discuss selective neuronal vulnerability, which still remains largely enigmatic.

KEYWORDS:

Alzheimer’s disease; Amyotrophic lateral sclerosis; Frontotemporal dementia; Huntington’s disease; Lou Gehrig’s disease; Parkinson’s disease; Polyglutamine diseases; Protein inclusions; Stress granules

PMID:
29947927
PMCID:
PMC6063327
DOI:
10.1007/s00018-018-2854-4
[Indexed for MEDLINE]
Free PMC Article

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