Neurodegenerative diseases: model organisms, pathology and autophagy

被引:18
作者
Suresh, S. N. [1 ]
Verma, Vijaya [2 ]
Sateesh, Shruthi [2 ]
Clement, James P. [2 ]
Manjithaya, Ravi [1 ,2 ]
机构
[1] Jawaharlal Nehru Ctr Adv Sci Res JNCASR, Mol Biol & Genet Unit, Jakkur 560064, Bengaluru, India
[2] Jawaharlal Nehru Ctr Adv Sci Res JNCASR, Neurosci Unit, Jakkur 560064, Bengaluru, India
基金
英国惠康基金;
关键词
neurodegeneration; aggrephagy; small molecule therapeutics; AMYOTROPHIC-LATERAL-SCLEROSIS; LONG-TERM POTENTIATION; YAC128 MOUSE MODEL; MEDIUM SPINY NEURONS; IN-VIVO ANALYSIS; HUNTINGTONS-DISEASE; ALZHEIMERS-DISEASE; SYNAPTIC PLASTICITY; PARKINSONS-DISEASE; TRANSGENIC MICE;
D O I
10.1007/s12041-018-0955-3
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
A proteostasis view of neurodegeneration (ND) identifies protein aggregation as a leading causative reason for damage seen at the cellular and organ levels. While investigative therapies that aim at dissolving aggregates have failed, and the promises of silencing expression of ND associated pathogenic proteins or the deployment of engineered induced pluripotent stem cells (iPSCs) are still in the horizon, emerging literature suggests degrading aggregates through autophagy-related mechanisms hold the current potential for a possible cure. Macroautophagy (hereafter autophagy) is an intracellular degradative pathway where superfluous or unwanted cellular cargoes (such as peroxisomes, mitochondria, ribosomes, intracellular bacteria and misfolded protein aggregates) are wrapped in double membrane vesicles called autophagosomes that eventually fuses with lysosomes for their degradation. The selective branch of autophagy that deals with identification, capture and degradation of protein aggregates is called aggrephagy. Here, we cover the workings of aggrephagy detailing its selectivity towards aggregates. The diverse cellular adaptors that bridge the aggregates with the core autophagy machinery in terms of autophagosome formation are discussed. In ND, essential protein quality control mechanisms fail as the constituent components also find themselves trapped in the aggregates. Thus, although cellular aggrephagy has the potential to be upregulated, its dysfunction further aggravates the pathogenesis. This phenomenon when combined with the fact that neurons can neither dilute out the aggregates by cell division nor the dead neurons can be replaced due to low neurogenesis, makes a compelling case for aggrephagy pathway as a potential therapeutic option.
引用
收藏
页码:679 / 701
页数:23
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