Editorial: Parkinson's disease: cell vulnerability and disease progression.

Javier Blesa,Jose L Lanciego,Jose A Obeso

doi:10.3389/fnana.2015.00125

Abstract

The hallmark of Parkinson Disease (PD) is the degeneration of dopaminergic neurons in thesubstantia nigra pars compacta (SNc) and the consequent striatal dopamine (DA) deﬁciency,although it is well recognized that neurodegeneration in PD goes beyond the SNc. Major advanceshave occurred in recent years on the molecular and pathophysiological basis of PD, howeverthere remain many questions and unknowns regarding SNc cells vulnerability, and the exactsigniﬁcance of Lewy bodies and alpha-synuclein (α-syn) aggregation process regarding diseaseonset and progression. This Research Topic discuss the etiopathogenesis of PD, presenting aseries of papers that provide up-to-date, state-of-the-art information on molecular and cellularmechanisms involved in the neurodegeneration process, neuroimmune pathways, the role offunctionalandanatomicalorganizationofthebasalgangliaasafactorofneuronalvulnerability,thepossibilitythatPDisapriondiseaseandthecellularresponsetoα-synaggregation.Understandingthe mechanisms underlying vulnerability of dopaminergic midbrain neurons and how pathologybecomes widespread are primary objectives of basic and clinical research in PD.Are dopaminergic and other neurons dying by the same pathogenic mechanisms? Do they alldietothesameextentoratthesamerate?Whatarethemoleculardeterminantsofsusceptibilitytothe disease? To gain insights into these questions, researchers mainly rely in animal models. Blesaand Przedborski (2014) provide a summary of the current knowledge of invivomodels of PD.Whereas PD can be sporadic, genetic or possibly related with toxic/infectious agents, a diﬀerentialpattern of cell loss among midbrain dopaminergic neurons is observed regardless of diseaseetiology suggesting that diﬀerential dopaminergic neuron vulnerability does not depend on thefactor triggering PD “perse” but on intrinsic properties of these speciﬁc cell groups. Here, Brichtaand Greengard (2014) provides an update review on the molecular basis underlying diﬀerentialvulnerability of midbrain dopaminergic neurons in PD. For example, for many years many studieshavesuggestedcalbindin(CB)asamarkertodistinguishbetweenmidbraindopaminergicneuronswithdiﬀerentsusceptibilitytodegenerationinPD.AlthoughCBdopaminergicneuronsseemtobeless prone to MPTP-induced degeneration, Dopeso-Reyes et al. (2014) clearly demonstrated thattheseneuronsarenotgivingrisetonigro-striatalprojectionsandindeedCB-ir/TH-irneuronsonlyoriginate nigro-extrastriatal projections. This data sustain the presence of a potential imbalancebetweenthenigro-striatalandnigroextrastriatalsystemsinadvanceddiseasesstates.Also,Afonso-Oramas et al. (2014) revealed that midbrain dopaminergic axons are in close apposition to striatalvessels and perivascular astrocytes in rats and monkeys. The relative weight of this “vascularcomponent” within the meso-striatal pathway suggests a role in the pathophysiology of PD.Aging is another major risk factor for developing PD. Rodriguez et al. (2014) reviewedsimilarities between neurodegeneration in PD and aging. The progressive course of aging andPD could be induced by the same multi-factorial etiology, including astrocytic and microgliaalterations, anomalous action of diﬀerent proteins, mitochondrial disturbances, alterations of themitophagy or the ubiquitin-proteasome system and oxidative stress. Proteins involved in PD suchas α-syn, PINK1 or DJ-1, are also involved in aging. All these mechanisms of degeneration are

Highlights

The hallmark of Parkinson Disease (PD) is the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the consequent striatal dopamine (DA) deficiency, it is well recognized that neurodegeneration in PD goes beyond the SNc
This Research Topic discuss the etiopathogenesis of PD, presenting a series of papers that provide up-to-date, state-of-the-art information on molecular and cellular mechanisms involved in the neurodegeneration process, neuroimmune pathways, the role of functional and anatomical organization of the basal ganglia as a factor of neuronal vulnerability, the possibility that PD is a prion disease and the cellular response to α-syn aggregation
Are dopaminergic and other neurons dying by the same pathogenic mechanisms? Do they all die to the same extent or at the same rate? What are the molecular determinants of susceptibility to the disease? To gain insights into these questions, researchers mainly rely in animal models

Summary

Introduction

The hallmark of Parkinson Disease (PD) is the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the consequent striatal dopamine (DA) deficiency, it is well recognized that neurodegeneration in PD goes beyond the SNc. Major advances have occurred in recent years on the molecular and pathophysiological basis of PD, there remain many questions and unknowns regarding SNc cells vulnerability, and the exact significance of Lewy bodies and alpha-synuclein (α-syn) aggregation process regarding disease onset and progression. This Research Topic discuss the etiopathogenesis of PD, presenting a series of papers that provide up-to-date, state-of-the-art information on molecular and cellular mechanisms involved in the neurodegeneration process, neuroimmune pathways, the role of functional and anatomical organization of the basal ganglia as a factor of neuronal vulnerability, the possibility that PD is a prion disease and the cellular response to α-syn aggregation.

Results

Conclusion