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, although 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, however 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. Understanding
the mechanisms underlying vulnerability of dopaminergic midbrain neurons and how pathology
becomes widespread are primary objectives of basic and clinical research in PD.
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. Blesa and Przedborski (2014) provide a summary of the
current knowledge of in vivo models of PD. Whereas PD can be sporadic, genetic or
possibly related with toxic/infectious agents, a differential pattern of cell loss
among midbrain dopaminergic neurons is observed regardless of disease etiology suggesting
that differential dopaminergic neuron vulnerability does not depend on the factor
triggering PD “per se” but on intrinsic properties of these specific cell groups.
Here, Brichta and Greengard (2014) provides an update review on the molecular basis
underlying differential vulnerability of midbrain dopaminergic neurons in PD. For
example, for many years many studies have suggested calbindin (CB) as a marker to
distinguish between midbrain dopaminergic neurons with different susceptibility to
degeneration in PD. Although CB dopaminergic neurons seem to be less prone to MPTP-induced
degeneration, Dopeso-Reyes et al. (2014) clearly demonstrated that these neurons are
not giving rise to nigro-striatal projections and indeed CB-ir/TH-ir neurons only
originate nigro-extrastriatal projections. This data sustain the presence of a potential
imbalance between the nigro-striatal and nigroextrastriatal systems in advanced diseases
states. Also, Afonso-Oramas et al. (2014) revealed that midbrain dopaminergic axons
are in close apposition to striatal vessels and perivascular astrocytes in rats and
monkeys. The relative weight of this “vascular component” 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) reviewed
similarities between neurodegeneration in PD and aging. The progressive course of
aging and PD could be induced by the same multi-factorial etiology, including astrocytic
and microglia alterations, anomalous action of different proteins, mitochondrial disturbances,
alterations of the mitophagy or the ubiquitin-proteasome system and oxidative stress.
Proteins involved in PD such as α-syn, PINK1 or DJ-1, are also involved in aging.
All these mechanisms of degeneration are review here giving an update of the classical
pathways, the biochemical and molecular events that mediate DA neuronal vulnerability,
and the role of PD-associated gene products in modulating cellular responses to oxidative
stress (Blesa et al., 2015). Additionally, Labandeira-García et al. (2014) discuss
the role of renin-angiotensin system in oxidative stress, aging and inflammation in
the nigrostriatal dopaminergic system. Inflammation is indeed a major characteristic
feature of the SNc in PD mainly as a consequence of neuronal death. Herrero et al.
(2015) review the role of inflammation and glucocorticoids in PD while Cebrián et
al. (2014) review the neuronal MHC-I expression in the SNc and its implications in
synaptic function, axonal regeneration in PD and other brain diseases.
The dopaminergic neurons of the SNc project primarily to the striatum, but also provide
significant innervation of other basal ganglia nuclei and the thalamus. Villalba et
al. (2015) discuss evidence for synaptic glutamatergic dysfunction and pathology of
cortical and thalamic inputs to the striatum and subthalamic nucleus in models of
PD. The altered neuronal firing activity of the basal ganglia and other nuclei contribute
largely to parkinsonisms. Galvan et al. (2015) reviewed the current knowledge of the
electrophysiologic changes at the single cell level, the level of local populations
of neural elements, and the entire basal ganglia-thalamocortical network in PD, and
discuss the possible use of this information to optimize treatment approaches. Neuroprotection
by endogenous glial cell-derived neurotrophic factor (GDNF) stimulation has been suggested
as one of the potential preventive therapies in PD for many years. In this issue d'Anglemont
de Tassigny et al. (2015) summarize current knowledge on brain GDNF delivery, homeostasis,
and its effects on SNc neurons and discuss the therapeutic potential of endogenous
GDNF stimulation in PD.
Formation and accumulation of misfolded α-syn aggregates are a central and very hot
topic of PD research currently. Several authors review and discuss here the importance
of this protein, it's role in different cellular domains (Guardia-Laguarta et al.,
2015), the pathophysiological mechanisms connecting α-syn and lysosomal dysfunction
in neuronal cell death (Bourdenx et al., 2014), how this protein can undergo a toxic
conformational change, spread from cell to cell and from region to region, and initiate
the formation of aggregates (Recasens and Dehay, 2014), and its possible relation
to other neurodegenerative diseases like progressive supranuclear palsy (Erro Aguirre
et al., 2015).
While all the features summarized above play a significant role in nigro-striatal
neurodegeneration, it is unlikely that the origin of neurodegeneration in PD could
be tight to a single pathogenic mechanism, hence the importance of defining markers
and features of neuronal vulnerability. Obeso's group introduces here the interesting
hypothesis that Parkinson's disease could be related and ultimately be the consequence
of human multi-tasking behavior (Hernandez et al., 2015). Thus, the caudal region
of the striatum has been associated with habitual behavior, consequently the differential
loss of DA from this region provides the pathophysiological substrate for the early
impairment of automatic movements (walking, writing…) and probably increased functional
demand during multiple and simultaneous tasks performance.
In sum, understanding the mechanisms responsible for intrinsic SNc neuronal vulnerability
is mandatory to progress in stopping neurodegeneration in PD. We trust that this Research
Topic will spark new ideas and foster further advances in PD.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.