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Selective neuronal vulnerability in Parkinson disease

Key Points

  • Clinical Parkinson disease (cPD) is associated with both distributed Lewy pathology (LP) and neuronal death. There are no proven strategies of modifying either feature of the disease.

  • Although there is consistency in the brain regions manifesting LP, there is considerable variability in its sequencing and severity. Moreover, the relationship between LP and the pathophysiology underlying symptoms is uncertain.

  • The distribution of LP in cPD is not consistent with a simple prion model in which the spread of LP is retrograde and determined solely by the brain connectome.

  • Neuronal death in cPD is less well characterized, but it is seen first in the substantia nigra, appearing later in a subset of neurons in the diencephalon, telencephalon and brainstem. Importantly, the pattern of neuronal death differs considerably in staging and to a lesser extent in distribution from that of LP.

  • Many of the neurons that die in cPD exhibit a common set of traits, which include a long, highly branched axon, autonomous spiking, elevated calcium entry and basal mitochondrial oxidant stress. This set of traits may make these neurons vulnerable to cell death in association with LP, ageing, genetic mutations associated with cPD and/or environmental toxins.

  • Therapeutic strategies aimed at altering the features of neurons that make them vulnerable to death and LP have the potential to slow or stop the progression of cPD.

Abstract

Intracellular α-synuclein (α-syn)-rich protein aggregates called Lewy pathology (LP) and neuronal death are commonly found in the brains of patients with clinical Parkinson disease (cPD). It is widely believed that LP appears early in the disease and spreads in synaptically coupled brain networks, driving neuronal dysfunction and death. However, post-mortem analysis of human brains and connectome-mapping studies show that the pattern of LP in cPD is not consistent with this simple model, arguing that, if LP propagates in cPD, it must be gated by cell- or region-autonomous mechanisms. Moreover, the correlation between LP and neuronal death is weak. In this Review, we briefly discuss the evidence for and against the spreading LP model, as well as evidence that cell-autonomous factors govern both α-syn pathology and neuronal death.

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Figure 1: Staging of Lewy pathology in clinical Parkinson disease.
Figure 2: Does connectivity predict Lewy pathology in clinical Parkinson disease?
Figure 3: Staging of neurodegeneration in clinical Parkinson disease.
Figure 4: How cell-autonomous factors might contribute to Lewy pathology and cell death in clinical Parkinson disease.

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Acknowledgements

This work was supported by US National Institutes of Health grant NS047085 and grants from the JPB Foundation and the IDP Foundation (to D.J.S.). G.M.H. is a National Health and Medical Research Council of Australia Senior Principal Research Fellow (grant #1079679). J.A.O.'s research is supported by grants SAF2012-40216 and SAF2015-67239-P from the Plan Nacional, Ministerio de Economía y Competitividad, Spain.

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Correspondence to D. James Surmeier, José A. Obeso or Glenda M. Halliday.

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Glossary

Lewy pathology

(LP). Abnormal, proteinaceous aggregates in the neuronal cytoplasm that are rich in α-synuclein.

Connectome

A detailed map of the synaptic connections that are formed between neurons in the brain.

Levodopa

The precursor to the neurotransmitter dopamine; it is given to patients with Parkinson disease because, unlike dopamine, it can pass through the blood–brain barrier and elevate brain dopamine concentrations.

Lewy neurites

Lewy pathology found within neuronal processes, including axons and dendrites.

Mitophagy

A form of autophagy in which damaged mitochondria are degraded.

Apoptosis

A process of programmed cell death involving activation of caspase signalling cascades that are commonly triggered by release of cytochrome c from mitochondria.

Necrosis

A form of cell death that is distinct from apoptosis and that is commonly caused by infection, toxins or ischaemia.

Mitochondrial redox

The state of reduction–oxidation reactions in mitochondria.

Phenocopies

In this case, neurons with a similar set of traits (for example, activity patterns) resulting from the interaction between their genome and the environment.

Dihydropyridine

A class of US-approved drugs that are negative allosteric modulators of Ca2+ channels with a Cav1 pore-forming subunit.

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Surmeier, D., Obeso, J. & Halliday, G. Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 18, 101–113 (2017). https://doi.org/10.1038/nrn.2016.178

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