Journal
TRENDS IN NEUROSCIENCES
Volume 43, Issue 7, Pages 475-492Publisher
CELL PRESS
DOI: 10.1016/j.tins.2020.05.001
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Funding
- 'Fonds National de Recherche', Luxembourg [FNR/06/04/05]
- Foundation Think, Luxembourg
- Rotary Luxembourg
- JSPS KAKENHI [17H03555, 16K14572]
- Swedish Research Council [MH-3026]
- HBP-Horizon 2020
- NIH
- Michael J. Fox Foundation D
- Rotary International
- Grants-in-Aid for Scientific Research [16K14572, 17H03555] Funding Source: KAKEN
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In this review, we approach Parkinson's disease (PD) in the context of an evolutionary mismatch of central nervous system functions. The neurons at risk have hyperbranched axons, extensive transmitter release sites, display spontaneous spiking, and elevated mitochondrial stress. They function in networks largely unchanged throughout vertebrate evolution, but now connecting to the expanded human cortex. Their breakdown is favoured by longevity. At the cellular level, mitochondrial dysfunction starts at the synapses, then involves axons and cell bodies. At the behavioural level, network dysfunctions provoke the core motor syndrome of parkinsonism including freezing and failed gait automatization, and non-motor deficits including inactive blindsight and autonomic dysregulation. The proposed evolutionary reinterpretation of PD-prone cellular phenotypes and of prototypical clinical symptoms allows a new conceptual framework for future research.
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