Loss-of-function of GNAL dystonia gene impairs striatal dopamine receptors-mediated adenylyl cyclase/ cyclic AMP signaling pathway.

Loss-of-function mutations in the GNAL gene are responsible for DYT-GNAL dystonia. However, how GNAL mutations contribute to synaptic dysfunction is still unclear. The GNAL gene encodes the Gαolf protein, an isoform of stimulatory Gαs enriched in the striatum, with a key role in the regulation of cAMP signaling. Here, we used a combined biochemical and electrophysiological approach to study GPCR-mediated AC-cAMP cascade in the striatum of the heterozygous GNAL (GNAL+/-) rat model. We first analyzed adenosine type 2 (A2AR), and dopamine type 1 (D1R) receptors, which are directly coupled to Gαolf, and observed that the total levels of A2AR were increased, whereas D1R level was unaltered in GNAL+/- rats. In addition, the striatal isoform of adenylyl cyclase (AC5) was reduced, despite unaltered basal cAMP levels. Notably, the protein expression level of dopamine type 2 receptor (D2R), that inhibits the AC5-cAMP signaling pathway, was also reduced, similar to what observed in different DYT-TOR1A dystonia models. Accordingly, in the GNAL+/- rat striatum we found altered levels of the D2R regulatory proteins, RGS9-2, spinophilin, Gß5 and ß-arrestin2, suggesting a downregulation of D2R signaling cascade. Additionally, by analyzing the responses of striatal cholinergic interneurons to D2R activation, we found that the receptor-mediated inhibitory effect is significantly attenuated in GNAL+/- interneurons. Altogether, our findings demonstrate a profound alteration in the A2AR/D2R-AC-cAMP cascade in the striatum of the rat DYT-GNAL dystonia model, and provide a plausible explanation for our previous findings on the loss of dopamine D2R-dependent corticostriatal long-term depression.

Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neuron Functions.

The human brain has hundreds of billions of neurons and at least 7 million dendrites have been hypothesized to exist for each neuron, with over 100 trillion neuron-neuron, neuron-muscle, and neuron-endocrine cell synapses [...].

Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process.

Due to the success of the first Special Issue on synaptic plasticity, I endeavored to promote a new Special Issue with an emphasis on dynamic changes in neuronal functions and physiological and pathological processes [...].

Mitochondrial Bioenergy in Neurodegenerative Disease: Huntington and Parkinson.

Strong evidence suggests a correlation between degeneration and mitochondrial deficiency. Typical cases of degeneration can be observed in physiological phenomena (i.e., ageing) as well as in neurological neurodegenerative diseases and cancer. All these pathologies have the dyshomeostasis of mitochondrial bioenergy as a common denominator. Neurodegenerative diseases show bioenergetic imbalances in their pathogenesis or progression. Huntington's chorea and Parkinson's disease are both neurodegenerative diseases, but while Huntington's disease is genetic and progressive with early manifestation and severe penetrance, Parkinson's disease is a pathology with multifactorial aspects. Indeed, there are different types of Parkinson/Parkinsonism. Many forms are early-onset diseases linked to gene mutations, while others could be idiopathic, appear in young adults, or be post-injury senescence conditions. Although Huntington's is defined as a hyperkinetic disorder, Parkinson's is a hypokinetic disorder. However, they both share a lot of similarities, such as neuronal excitability, the loss of striatal function, psychiatric comorbidity, etc. In this review, we will describe the start and development of both diseases in relation to mitochondrial dysfunction. These dysfunctions act on energy metabolism and reduce the vitality of neurons in many different brain areas.

Oxidative stress and synaptic dysfunction in rodent models of Parkinson's disease.

Parkinson's disease (PD) is a multifactorial disorder involving a complex interplay between a variety of genetic and environmental factors. In this scenario, mitochondrial impairment and oxidative stress are widely accepted as crucial neuropathogenic mechanisms, as also evidenced by the identification of PD-associated genes that are directly involved in mitochondrial function. The concept of mitochondrial dysfunction is closely linked to that of synaptic dysfunction. Indeed, compelling evidence supports the role of mitochondria in synaptic transmission and plasticity, although many aspects have not yet been fully elucidated. Here, we will provide a brief overview of the most relevant evidence obtained in different neurotoxin-based and genetic rodent models of PD, focusing on mitochondrial impairment and synaptopathy, an early central event preceding overt nigrostriatal neurodegeneration. The identification of early deficits occurring in PD pathogenesis is crucial in view of the development of potential disease-modifying therapeutic strategies.

Alpha-Synuclein is Involved in DYT1 Dystonia Striatal Synaptic Dysfunction.

BACKGROUND: The neuronal protein alpha-synuclein (α-Syn) is crucially involved in Parkinson's disease pathophysiology. Intriguingly, torsinA (TA), the protein causative of DYT1 dystonia, has been found to accumulate in Lewy bodies and to interact with α-Syn. Both proteins act as molecular chaperones and control synaptic machinery. Despite such evidence, the role of α-Syn in dystonia has never been investigated. OBJECTIVE: We explored whether α-Syn and N-ethylmaleimide sensitive fusion attachment protein receptor proteins (SNAREs), that are known to be modulated by α-Syn, may be involved in DYT1 dystonia synaptic dysfunction. METHODS: We used electrophysiological and biochemical techniques to study synaptic alterations in the dorsal striatum of the Tor1a+ /Δgag mouse model of DYT1 dystonia. RESULTS: In the Tor1a+/Δgag DYT1 mutant mice, we found a significant reduction of α-Syn levels in whole striata, mainly involving glutamatergic corticostriatal terminals. Strikingly, the striatal levels of the vesicular SNARE VAMP-2, a direct α-Syn interactor, and of the transmembrane SNARE synaptosome-associated protein 23 (SNAP-23), that promotes glutamate synaptic vesicles release, were markedly decreased in mutant mice. Moreover, we detected an impairment of miniature glutamatergic postsynaptic currents (mEPSCs) recorded from striatal spiny neurons, in parallel with a decreased asynchronous release obtained by measuring quantal EPSCs (qEPSCs), which highlight a robust alteration in release probability. Finally, we also observed a significant reduction of TA striatal expression in α-Syn null mice. CONCLUSIONS: Our data demonstrate an unprecedented relationship between TA and α-Syn, and reveal that α-Syn and SNAREs alterations characterize the synaptic dysfunction underlying DYT1 dystonia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Autism Spectrum Disorder: Focus on Glutamatergic Neurotransmission.

Disturbances in the glutamatergic system have been increasingly documented in several neuropsychiatric disorders, including autism spectrum disorder (ASD). Glutamate-centered theories of ASD are based on evidence from patient samples and postmortem studies, as well as from studies documenting abnormalities in glutamatergic gene expression and metabolic pathways, including changes in the gut microbiota glutamate metabolism in patients with ASD. In addition, preclinical studies on animal models have demonstrated glutamatergic neurotransmission deficits and altered expression of glutamate synaptic proteins. At present, there are no approved glutamatergic drugs for ASD, but several ongoing clinical trials are currently focusing on evaluating in autistic patients glutamatergic pharmaceuticals already approved for other conditions. In this review, we provide an overview of the literature concerning the role of glutamatergic neurotransmission in the pathophysiology of ASD and as a potential target for novel treatments.

Pattern of Mitochondrial Respiration in Peripheral Blood Cells of Patients with Parkinson's Disease.

Mitochondria are central in the pathogenesis of Parkinson's disease (PD), as they are involved in oxidative stress, synaptopathy, and other immunometabolic pathways. Accordingly, they are emerging as a potential neuroprotection target, although further human-based evidence is needed for therapeutic advancements. This study aims to shape the pattern of mitochondrial respiration in the blood leukocytes of PD patients in relation to both clinical features and the profile of cerebrospinal fluid (CSF) biomarkers of neurodegeneration. Mitochondrial respirometry on the peripheral blood mononucleate cells (PBMCs) of 16 PD patients and 14 controls was conducted using Seahorse Bioscience technology. Bioenergetic parameters were correlated either with standard clinical scores for motor and non-motor disturbances or with CSF levels of α-synuclein, amyloid-ß peptides, and tau proteins. In PD, PBMC mitochondrial basal respiration was normal; maximal and spare respiratory capacities were both increased; and ATP production was higher, although not significantly. Maximal and spare respiratory capacity was directly correlated with disease duration, MDS-UPDRS part III and Hoehn and Yahr motor scores; spare respiratory capacity was correlated with the CSF amyloid-ß-42 to amyloid-ß-42/40 ratio. We provided preliminary evidence showing that mitochondrial respiratory activity increases in the PBMCs of PD patients, probably following the compensatory adaptations to disease progression, in contrast to the bases of the neuropathological substrate.

CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors.

CalDAG-GEFI (CDGI) is a protein highly enriched in the striatum, particularly in the principal spiny projection neurons (SPNs). CDGI is strongly down-regulated in two hyperkinetic conditions related to striatal dysfunction: Huntington's disease and levodopa-induced dyskinesia in Parkinson's disease. We demonstrate that genetic deletion of CDGI in mice disrupts dendritic, but not somatic, M1 muscarinic receptors (M1Rs) signaling in indirect pathway SPNs. Loss of CDGI reduced temporal integration of excitatory postsynaptic potentials at dendritic glutamatergic synapses and impaired the induction of activity-dependent long-term potentiation. CDGI deletion selectively increased psychostimulant-induced repetitive behaviors, disrupted sequence learning, and eliminated M1R blockade of cocaine self-administration. These findings place CDGI as a major, but previously unrecognized, mediator of cholinergic signaling in the striatum. The effects of CDGI deletion on the self-administration of drugs of abuse and its marked alterations in hyperkinetic extrapyramidal disorders highlight CDGI's therapeutic potential.

Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia.

BACKGROUND: Acetylcholine-mediated transmission plays a central role in the impairment of corticostriatal synaptic activity and plasticity in multiple DYT1 mouse models. However, the nature of such alteration remains unclear. OBJECTIVE: The aim of the present work was to characterize the mechanistic basis of cholinergic dysfunction in DYT1 dystonia to identify potential targets for pharmacological intervention. METHODS: We utilized electrophysiology recordings, immunohistochemistry, enzymatic activity assays, and Western blotting techniques to analyze in detail the cholinergic machinery in the dorsal striatum of the Tor1a+/- mouse model of DYT1 dystonia. RESULTS: We found a significant increase in the vesicular acetylcholine transporter (VAChT) protein level, the protein responsible for loading acetylcholine (ACh) from the cytosol into synaptic vesicles, which indicates an altered cholinergic tone. Accordingly, in Tor1a+/- mice we measured a robust elevation in basal ACh content coupled to a compensatory enhancement of acetylcholinesterase (AChE) enzymatic activity. Moreover, pharmacological activation of dopamine D2 receptors, which is expected to reduce ACh levels, caused an abnormal elevation in its content, as compared to controls. Patch-clamp recordings revealed a reduced effect of AChE inhibitors on cholinergic interneuron excitability, whereas muscarinic autoreceptor function was preserved. Finally, we tested the hypothesis that blockade of VAChT could restore corticostriatal long-term synaptic plasticity deficits. Vesamicol, a selective VAChT inhibitor, rescued a normal expression of synaptic plasticity. CONCLUSIONS: Overall, our findings indicate that VAChT is a key player in the alterations of striatal plasticity and a novel target to normalize cholinergic dysfunction observed in DYT1 dystonia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A2A Receptor Dysregulation in Dystonia DYT1 Knock-Out Mice.

We aimed to investigate A2A receptors in the basal ganglia of a DYT1 mouse model of dystonia. A2A was studied in control Tor1a+/+ and Tor1a+/- knock-out mice. A2A expression was assessed by anti-A2A antibody immunofluorescence and Western blotting. The co-localization of A2A was studied in striatal cholinergic interneurons identified by anti-choline-acetyltransferase (ChAT) antibody. A2A mRNA and cyclic adenosine monophosphate (cAMP) contents were also assessed. In Tor1a+/+, Western blotting detected an A2A 45 kDa band, which was stronger in the striatum and the globus pallidus than in the entopeduncular nucleus. Moreover, in Tor1a+/+, immunofluorescence showed A2A roundish aggregates, 0.3-0.4 µm in diameter, denser in the neuropil of the striatum and the globus pallidus than in the entopeduncular nucleus. In Tor1a+/-, A2A Western blotting expression and immunofluorescence aggregates appeared either increased in the striatum and the globus pallidus, or reduced in the entopeduncular nucleus. Moreover, in Tor1a+/-, A2A aggregates appeared increased in number on ChAT positive interneurons compared to Tor1a+/+. Finally, in Tor1a+/-, an increased content of cAMP signal was detected in the striatum, while significant levels of A2A mRNA were neo-expressed in the globus pallidus. In Tor1a+/-, opposite changes of A2A receptors' expression in the striatal-pallidal complex and the entopeduncular nucleus suggest that the pathophysiology of dystonia is critically dependent on a composite functional imbalance of the indirect over the direct pathway in basal ganglia.

Impaired dopamine- and adenosine-mediated signaling and plasticity in a novel rodent model for DYT25 dystonia.

Dystonia is a neurological movement disorder characterized by sustained or intermittent involuntary muscle contractions. Loss-of-function mutations in the GNAL gene have been identified to be the cause of "isolated" dystonia DYT25. The GNAL gene encodes for the guanine nucleotide-binding protein G(olf) subunit alpha (Gαolf), which is mainly expressed in the olfactory bulb and the striatum and functions as a modulator during neurotransmission coupling with D1R and A2AR. Previously, heterozygous Gαolf -deficient mice (Gnal+/-) have been generated and showed a mild phenotype at basal condition. In contrast, homozygous deletion of Gnal in mice (Gnal-/-) resulted in a significantly reduced survival rate. In this study, using the CRISPR-Cas9 system we generated and characterized heterozygous Gnal knockout rats (Gnal+/-) with a 13 base pair deletion in the first exon of the rat Gnal splicing variant 2, a major isoform in both human and rat striatum. Gnal+/- rats showed early-onset phenotypes associated with impaired dopamine transmission, including reduction in locomotor activity, deficits in rotarod performance and an abnormal motor skill learning ability. At cellular and molecular level, we found down-regulated Arc expression, increased cell surface distribution of AMPA receptors, and the loss of D2R-dependent corticostriatal long-term depression (LTD) in Gnal+/- rats. Based on the evidence that D2R activity is normally inhibited by adenosine A2ARs, co-localized on the same population of striatal neurons, we show that blockade of A2ARs restores physiological LTD. This animal model may be a valuable tool for investigating Gαolf function and finding a suitable treatment for dystonia associated with deficient dopamine transmission.

Loss of Non-Apoptotic Role of Caspase-3 in the PINK1 Mouse Model of Parkinson's Disease.

Caspases are a family of conserved cysteine proteases that play key roles in multiple cellular processes, including programmed cell death and inflammation. Recent evidence shows that caspases are also involved in crucial non-apoptotic functions, such as dendrite development, axon pruning, and synaptic plasticity mechanisms underlying learning and memory processes. The activated form of caspase-3, which is known to trigger widespread damage and degeneration, can also modulate synaptic function in the adult brain. Thus, in the present study, we tested the hypothesis that caspase-3 modulates synaptic plasticity at corticostriatal synapses in the phosphatase and tensin homolog (PTEN) induced kinase 1 (PINK1) mouse model of Parkinson's disease (PD). Loss of PINK1 has been previously associated with an impairment of corticostriatal long-term depression (LTD), rescued by amphetamine-induced dopamine release. Here, we show that caspase-3 activity, measured after LTD induction, is significantly decreased in the PINK1 knockout model compared with wild-type mice. Accordingly, pretreatment of striatal slices with the caspase-3 activator α-(Trichloromethyl)-4-pyridineethanol (PETCM) rescues a physiological LTD in PINK1 knockout mice. Furthermore, the inhibition of caspase-3 prevents the amphetamine-induced rescue of LTD in the same model. Our data support a hormesis-based double role of caspase-3; when massively activated, it induces apoptosis, while at lower level of activation, it modulates physiological phenomena, like the expression of corticostriatal LTD. Exploring the non-apoptotic activation of caspase-3 may contribute to clarify the mechanisms involved in synaptic failure in PD, as well as in view of new potential pharmacological targets.

The neurobiological bases of autism spectrum disorders: the R451C-neuroligin 3 mutation hampers the expression of long-term synaptic depression in the dorsal striatum.

Autism spectrum disorders (ASDs) comprise a heterogeneous group of disorders with a complex genetic etiology. Current theories on the pathogenesis of ASDs suggest that they might arise from an aberrant synaptic transmission affecting specific brain circuits and synapses. The striatum, which is part of the basal ganglia circuit, is one of the brain regions involved in ASDs. Mouse models of ASDs have provided evidence for an imbalance between excitatory and inhibitory neurotransmission. Here, we investigated the expression of long-term synaptic plasticity at corticostriatal glutamatergic synapses in the dorsal striatum of the R451C-NL3 phenotypic mouse model of autism. This mouse model carries the human R451C mutation in the neuroligin 3 (NL3) gene that has been associated with highly penetrant autism in a Swedish family. The R451C-NL3 mouse has been shown to exhibit autistic-like behaviors and alterations of synaptic transmission in different brain areas. However, excitatory glutamatergic transmission and its long-term plasticity have not been investigated in the dorsal striatum so far. Our results indicate that the expression of long-term synaptic depression (LTD) at corticostriatal glutamatergic synapses in the dorsal striatum is impaired by the R451C-NL3 mutation. A partial rescue of LTD was obtained by exogenous activation of cannabinoid CB1 receptors or enhancement of the endocannabinoid tone, suggesting that an altered cannabinoid drive might underlie the deficit of synaptic plasticity in the dorsal striatum of R451C-NL3 mice.

Early synaptic dysfunction in Parkinson's disease: Insights from animal models.

The appearance of motor manifestations in Parkinson's disease (PD) is invariably linked to degeneration of nigral dopaminergic neurons of the substantia nigra pars compacta. Traditional views on PD neuropathology have been grounded in the assumption that the prime event of neurodegeneration involves neuronal cell bodies with the accumulation of metabolic products. However, this view has recently been challenged by both clinical and experimental evidence. Neuropathological studies in human brain samples and both in vivo and in vitro models support the hypothesis that nigrostriatal synapses may indeed be affected at the earliest stages of the neurodegenerative process. The mechanisms leading to either structural or functional synaptic dysfunction are starting to be elucidated and include dysregulation of axonal transport, impairment of the exocytosis and endocytosis machinery, altered intracellular trafficking, and loss of corticostriatal synaptic plasticity. The aim of this review is to try to integrate different lines of evidence from both pathogenic and genetic animal models that, to different extents, suggest that early synaptic impairment may represent the key event in PD pathogenesis. Understanding the molecular and cellular events underlying such synaptopathy is a fundamental step toward developing specific biomarkers of early dopaminergic dysfunction and, more importantly, designing novel therapies targeting the synaptic apparatus of selective, vulnerable synapses. © 2016 International Parkinson and Movement Disorder Society.

Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors.

Broad-spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity of these drugs and their mechanism of action is not entirely clear. We performed a systematic analysis of the effects of anticholinergic drugs on short- and long-term plasticity recorded from striatal medium spiny neurons from DYT1 dystonia knock-in (Tor1a(+/Δgag) ) mice heterozygous for ΔE-torsinA and their controls (Tor1a(+/+) mice). Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, trihexyphenydil, biperiden, orphenadrine, and a novel selective M1 antagonist, VU0255035. Tor1a(+/Δgag) mice exhibited a significant impairment of corticostriatal synaptic plasticity. Anticholinergics had no significant effects on intrinsic membrane properties and on short-term plasticity of striatal neurons. However, they exhibited a differential ability to restore the corticostriatal plasticity deficits. A complete rescue of both long-term depression (LTD) and synaptic depotentiation (SD) was obtained by applying the M1 -preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the nonselective antagonist orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M1 receptors was further demonstrated by their ability to counteract the M1 -dependent potentiation of N-methyl-d-aspartate (NMDA) current recorded from striatal neurons. Our study demonstrates that selective M1 muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder.

PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity.

Homozygous or compound heterozygous mutations in the phosphatase and tensin homolog-induced putative kinase 1 (PINK1) gene are causative of autosomal recessive, early onset Parkinson's disease. Single heterozygous mutations have been detected repeatedly both in a subset of patients and in unaffected individuals, and the significance of these mutations has long been debated. Several neurophysiological studies from non-manifesting PINK1 heterozygotes have demonstrated the existence of neural plasticity abnormalities, indicating the presence of specific endophenotypic traits in the heterozygous state. We performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knockout (PINK1(+/-) ) mice using a multidisciplinary approach and observed that, despite normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depression was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, a significantly lower dopamine release was measured in the striatum of PINK1(+/-) mice compared with control mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmacological agents capable of increasing the availability of dopamine in the synaptic cleft restored normal LTP in heterozygous mice. Moreover, monoamine oxidase B inhibitors rescued physiological LTP and normal dopamine release. Our results provide novel evidence for striatal plasticity abnormalities, even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of Parkinson's disease and a valid tool with which to characterize early disease stage and design possible disease-modifying therapies.

Cholinergic dysfunction alters synaptic integration between thalamostriatal and corticostriatal inputs in DYT1 dystonia.

Projections from thalamic intralaminar nuclei convey sensory signals to striatal cholinergic interneurons. These neurons respond with a pause in their pacemaking activity, enabling synaptic integration with cortical inputs to medium spiny neurons (MSNs), thus playing a crucial role in motor function. In mice with the DYT1 dystonia mutation, stimulation of thalamostriatal axons, mimicking a response to salient events, evoked a shortened pause and triggered an abnormal spiking activity in interneurons. This altered pattern caused a significant rearrangement of the temporal sequence of synaptic activity mediated by M(1) and M(2) muscarinic receptors in MSNs, consisting of an increase in postsynaptic currents and a decrease of presynaptic inhibition, respectively. Consistent with a major role of acetylcholine, either lowering cholinergic tone or antagonizing postsynaptic M(1) muscarinic receptors normalized synaptic activity. Our data demonstrate an abnormal time window for synaptic integration between thalamostriatal and corticostriatal inputs, which might alter the action selection process, thereby predisposing DYT1 gene mutation carriers to develop dystonic movements.

Beyond the Microbiota: Understanding the Role of the Enteric Nervous System in Parkinson's Disease from Mice to Human.

The enteric nervous system (ENS) is a nerve network composed of neurons and glial cells that regulates the motor and secretory functions of the gastrointestinal (GI) tract. There is abundant evidence of mutual communication between the brain and the GI tract. Dysfunction of these connections appears to be involved in the pathophysiology of Parkinson's disease (PD). Alterations in the ENS have been shown to occur very early in PD, even before central nervous system (CNS) involvement. Post-mortem studies of PD patients have shown aggregation of α-synuclein (αS) in specific subtypes of neurons in the ENS. Subsequently, αS spreads retrogradely in the CNS through preganglionic vagal fibers to this nerve's dorsal motor nucleus (DMV) and other central nervous structures. Here, we highlight the role of the ENS in PD pathogenesis based on evidence observed in animal models and using a translational perspective. While acknowledging the putative role of the microbiome in the gut-brain axis (GBA), this review provides a comprehensive view of the ENS not only as a "second brain", but also as a window into the "first brain", a potentially crucial element in the search for new therapeutic approaches that can delay and even cure the disease.