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Review
. 2018 Oct;285(19):3657-3668.
doi: 10.1111/febs.14607. Epub 2018 Aug 14.

Determinants of Dopaminergic Neuron Loss in Parkinson's Disease

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Free PMC article
Review

Determinants of Dopaminergic Neuron Loss in Parkinson's Disease

Dalton James Surmeier. FEBS J. .
Free PMC article

Abstract

The cardinal motor symptoms of Parkinson's disease (PD) are caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Alpha-synuclein (aSYN) pathology and mitochondrial dysfunction have been implicated in PD pathogenesis, but until recently it was unclear why SNc dopaminergic neurons should be particularly vulnerable to these two types of insult. In this brief review, the evidence that SNc dopaminergic neurons have an anatomical, physiological, and biochemical phenotype that predisposes them to mitochondrial dysfunction and synuclein pathology is summarized. The recognition that certain traits may predispose neurons to PD-linked pathology creates translational opportunities for slowing or stopping disease progression.

Keywords: autophagy; axon; bioenergetics; calcium; dopamin; lewy pathology; mitochondria; synuclein.

Figures

Figure 1:
Figure 1:
Schematic summary of the key traits of neurons that are vulnerable in PD. Two major drivers of pathogenesis are mitochondrial and proteostatic dysfunction. Mitochondrial dysfunction is proposed to be a consequence of anticipatory (feed-forward) control of mitochondrial respiration by calcium, and yet undefined axonal bioenergetic factors working in combination with genetic and environmental factors (e.g., toxins). Proteostatic dysfunction is proposed to arise from aSYN aggregation promoted by oxidant stress, elevated cytosolic calcium and DA quinones, in addition to lysosomal dysfunction promoted by increased mitophagy and oxidant damage to lysosomal proteins like glucocerebrosidase. Solid lines make connections between events that are well-established in mammalian models; dashed lines connect mechanisms for which there is good but not unequivocal support.

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