Unraveling the molecular processes involved in the genesis, differentiation, and cell
death of the nervous system is an intense and continual interest of the neuroscience
community. In recent years, the preponderance of research focused upon signal transduction
mechanisms relying on protein cascades, but more information is needed on the role
and function of other molecular mechanisms. These molecular mechanisms include but
not limited to: lipid mediators (sphingolipids, fatty acids, glycerophospholipids,
etc.), lipid-binding proteins (ApoD, PPAR, etc.), protein-lipid interactions (c-Fos-lipid
synthesizing enzymes), protein misfolding and not fully characterized membrane-protein
receptors. Signal transduction events triggered by bioactive lipids and related transcription
factors (immediate early genes, metabolic regulators, etc.) now receive special attention
as an important nodal regulatory process. Deregulation of lipid-mediated processes
is also linked to neurodegenerative diseases [Parkinson (PD), Alzheimer (AD), and
retinopathies] and proliferative disorders (brain cancer and diabetic retinopathy).
Moreover, the modern lifestyle (hypercaloric diets, continuous artificial light exposure,
sedentary life, aging, stress) impacts on lipid signaling and metabolism, and can
alter brain function, physiology, and behavior. Focused on this broad spectrum of
underlying mechanisms related to molecular and cellular neuroscience, a Research Topic
call elicited expansive, research interest and submissions from among international
laboratories. As a result of this interest, 33 contributions are accepted and published
on the molecular mechanisms as described above. One hundred and fifty-eight authors
from research laboratories located in nine countries: North and South America (Argentina,
Canada, Chile, and USA), Asia (China), and Europe (France, Poland, Spain, Switzerland),
contributed to the accepted, peer-reviewed articles.
Glia-neuron Crosstalk From Biology to Pathophysiology
Interesting contributions to this Research Topic includes the characterizations of
the glia-neuron communication and interaction that is reported by Pascua-Maestro et
al. and Volonté et al. and reviewed by Barber and Raben. Particularly, Pascua-Maestro
et al. clearly demonstrated that glial cells rescue neurons exposed to cellular stress
by astrocyte-secreted extracellular vesicles loaded with the lipid binding protein:
ApoD. These observations highlighted the neuro-protective role of ApoD to promote
neuronal survival during oxidative stress. In the future, novel therapeutics may involve
ApoD-loaded exosomes because these exosomes can cross the blood-brain barrier to treat
neurodegenerative diseases. Astroglial cells secrete lipid signals that can modulate
functionally both presynaptic and postsynaptic neurotransmissions and consequently
brain activity. The lipid compositions of the pre- and post-synaptic membranes of
neurons impact functions involving vesicle fusion and receptor mobility, and strongly
suggest an essential lipid-mediated communication between glia and neurons. Nevertheless,
lipid metabolism controlling the interactions among different cell lineages is a new
frontier in neuroscience. Barber and Raben reviewed the published research on neuronal
and glial lipid metabolism, and reported mounting evidence that suggests a significant
impact of lipid metabolism on neurotransmission.
As part of the central nervous system, the vertebrate retina constitutes a suitable
model to investigate the effect of diverse extracellular signals [light, lipopolysaccharide
(LPS), oxygen levels, oxidative stress, etc.] under physiological and pathological
conditions. A number of papers investigated changes in fatty acid (FA) composition
and promotion of oxidative stress might be one of the pathways implicated in retinal
degeneration (RD) triggered by continuous LED light exposure of low intensity (Benedetto
and Contin). On the contrary, brief pulses of bright blue light cause photic responses
in Muller glial cell (MGCs) expressing novel non-visual opsins (Opn3 and Opn5) through
intracellular calcium mobilization without affecting cell viability (Rios et al.).
This prolonged photosensitivity may play a key role in the retinal physiology presumably
regulating cell to cell interaction and glia to neuron communication. In addition,
abnormal retina exposure to exogenous LPS administration or high oxygen levels shares
a common cellular mechanism of autophagy (Bermúdez et al.; Subirada et al.). Indeed,
autophagy mediates retinal pigment epithelium (RPE) cell survival through a pathway
modulated by Phospholipase D activity (Bermúdez et al.); whereas, it can also modulate
vascular, glial, and neuronal activities in an oxygen-induced retinopathy mouse model
(Subirada et al.). Strikingly, the pharmacological regulation of autophagy may offer
promising therapeutic strategies to reduce neovascular tufts, persistent gliosis together
with the promotion of cell survival in retinal inflammatory and degenerative diseases.
During retina degeneration as in retinitis pigmentosa, photoreceptors may be regenerated
by MGCs which acts as stem cells. Demonstrated by Volonté et al., there exists a defective
crosstalk between neurons and those MGCs in rd1 retinas that severely impairs the
regenerative potential of retinal stem cells. Furthermore, the crosstalk among non-neuronal
cells, such as: the RPE cells and retinal neurons, is extensively reviewed by Simón
et al. in relation to proliferation, survival, migration, neovascularization, inflammation,
and death of retinal cells.
Lipids and Beyond: New Insights on Function and Dysfunction in the Nervous System
Besides their structural role, lipids have pleiotropic functions in terms of intracellular
signaling and metabolism. Insights into lipid metabolism and signaling, lipid-protein
interaction, and lipid-binding proteins are topics of many new research papers and
reviews. Bioactive lipids inevitably are involved in both physiological and neuropathological
processes. FAs have relevant participation as secondary messengers in neuronal signaling.
Free FAs are ligands of different types of proteins, such as G-protein coupled receptors,
FA-binding proteins, and transcription factors of the Peroxisome Proliferator-Activated
Receptors family. The wide variety of signaling molecules modulated by free FAs determine
their importance in diverse cellular processes occurring in neurons and glial cells.
As new roles for these bioactive compounds are deciphered, new promissory therapeutic
targets are under consideration (Falomir-Lockhart et al.). The enzymes catalyzing
the elongation of very long chain FAs (ELOV) has been described as new players in
neuronal survival and synaptic signaling. ELOV4, one member of this elongase family,
expressed in neurons and several mutations in its encoding gene has been associated
with different neurological disorders (Stargardt-like macular dystrophy, spinocerebellar
ataxia 34, and others) (Deák et al.).
FA-signaling also participates in the sphingolipid rheostat in the retina. Sphingolipids
are a complex family of lipids including ceramide, ceramide 1-phosphate, and sphingosine
1-phosphate with relevant roles during development and in the degenerative diseases
onsets (Simón et al.). Docosahexaenoic acid, a major n-3 polyunsaturated FA in nervous
system, has been shown to protect photoreceptor cells from death through the modulation
of the sphingolipid rheostat by decreasing ceramide levels or by enhancing sphingosine
1-phosphate synthesis (Simón et al.).
Phosphatidic acid (PA) is another pleiotropic molecule exhibiting central roles in
glycerolipid metabolism and in cellular signaling. Produced by phospholipase D, PA
can bind and regulate the activity of an important number of cellular targets such
as nucleotide-binding proteins, kinases, and phosphatases. In consequence, deregulation
of PA production or catabolism are associated with synaptic dysfunction and several
neurological disorder, such as cognitive deficits related to AD, intellectual disability
diseases (Fragile-X and Coffin-Lowry syndromes) and fetal alcohol spectrum disorders
(Tanguy et al.).
Regarding biological membranes and neurodegenerative diseases such as in AD and PD,
a couple of impressive reviews summarizes most of the literature published over the
last decades (Alza et al.; Fabiani and Antollini). The article by Fabiani and Antollini
highlights the role of different lipids (cholesterol, PA, sphingomyelin, and gangliosides)
in nicotinic acetylcholine receptor function, and the crosstalk between amyloid processing,
cholinergic signaling and membrane lipid composition, reinforcing the relevance of
cholinergic hypothesis for AD. In contrast, lipid-binding properties of α-synuclein,
whose pathological aggregation and accumulation are hallmarks of PD has also been
described by Alza et al. highlighting the state of the art of how phospholipids, FAs
and their metabolisms participate in the pathological aggregation of this protein.
In the context of lipid biology, a transcription factor, c-FOS, may play a critical
role. This intriguing protein belongs to the Immediate Early Gene family and apart
from its role as transcription factor, has the unique characteristic of regulating
de novo biosynthesis of lipids and their enzymes by protein-protein interactions at
the endoplasmic reticulum. This novel function is essential for membrane biogenesis,
cell proliferation and neurite outgrowth, and involved in pathological conditions
such as brain tumors growth and development (Rodríguez-Berdini and Caputto).
Neurodegenerative Diseases: Understanding Normal Physiology Guides Intervention into
Pathology
To develop therapies and biomarkers for neurodegenerative diseases, one imperative
is to understand the normal physiology of the brain during development and aging.
Pro-survival and anti-toxic strategies are approaches to protect neurons and prevent
neurodegenerative diseases. In this issue, the use of neurotrophins in neuroprotective
strategies is reviewed by Saragovi et al.. Gestational, developmental, and nutritional
conditions may have permanent effects on the brain physiology. In this issue, the
contributions of Adamo et al. revealed the effects of marginal zinc deficiency (MZD)
during gestation. The researchers found major alterations in signal transduction pathways
in rats kept on an MDZ diet throughout gestation and beyond (i.e., ERK1/2, Sox2, etc.),
down-regulation of Pax6, Tbr2, and Tbr1 expression, a lower density of neurons and
a selective decrease of glutamatergic neurons in the young adult brain cortex. Collective
changes that can potentially result in behavioral impairment throughout life (Adamo
et al.).
Estrogens are characterized as signals involved in the sexual differentiation of the
brain. Recently, evidence highlighted the participation of estradiol, not only as
a reproductive hormone, but also as a brain derived neuronal, protective factor. The
coordination of estradiol signaling protects against neurodegenerative diseases and
cognitive decline. The work by Zapata et al. elucidates the mechanism of estradiol
to promote axonal growth showing that calcium mobilization from the extracellular
space and the endoplasmic reticulum is necessary for the ERK1/2 activation and axogenesis
in cultures of hypothalamic neurons.
One interesting aspect of signaling mechanisms is that receptor interactions at the
neuronal plasma membrane provide a level of regulation. In the report by Soto et al.
measurements of neuronal, plasma-membrane receptors co-localization and expression
obtained by immunological pull-down experiments in combination with TIRF microscopy
and AFM imaging demonstrated that P2X4/5-HT3A receptor complexes can interact with
each other in a 1:1 stoichiometric manner, and preserved after ATP binding. Additional
information on the receptor binding interaction and the allosteric regulation of its
activity is also provided.
Among the neurodegenerative diseases, prion-like protein aggregation is a typical
characteristic of each disease. Protein misfolding and signaling abnormalities is
correlated and causally related to neuronal pathology and the progression of neurodegeneration.
The mechanisms underlying the retrograde neurodegeneration remains elusive. In a review,
Zamponi and Pigino highlighted the involvement of fast axonal transport and CK2 activity
in the process of neurodegeneration in AD and prion disease. AD, the most common neurodegenerative
disease, is diagnosed by two main histopathological lesions: extracellular amyloid
plaques mainly composed by the beta-amyloid peptide (Aβ), and the intra-neuronal,
neurofibrillary tangles, mainly composed by hyperphosphorylated tau (HP-tau). In this
issue, Lasala et al. demonstrated that the interaction of Aβ directly affects α7 nicotinic
receptor by acting as an agonist and a negative modulator. Reduced α7 activity, in
the presence of higher Aβ concentrations or its long exposure, contribute to the cholinergic
signaling deficit, and may be involved in the initiation and development of AD. Moreover,
Morozova et al. presented evidence that the muscarinic cholinergic receptor M1/M3
is linked to the tau uptake by the neurons. The uptake of pathological HP-tau induced
neurite breakdown. The release and uptake of HP-tau might participate in the prion-like
transmission of the disease to neighboring neurons, and preventing this transmission
might provide basis for new therapeutic designs.
Concluding Remarks
In summary, the accumulation of novel research articles and reviews from this topic
call support the further expansion of research into cellular and molecular neurobiological
processes. Decoding the puzzle of these processes under physiological and pathological
conditions can pave the way to identify potential biomarkers and therapeutic targets
and novel treatments. A list of these contributions is appended bellow.
Author Contributions
MG and GS wrote Research Topic proposal. MG, GS, and AA wrote the editorial letter,
assigned reviewers, edited articles, and reviewed final manuscript. All authors contributed
to the article and approved the submitted version.
Conflict of Interest
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.