Exploration of Neuroprotective Therapy

Special Issue Topic

Role of the Monoaminergic Systems in the Pathogenesis and the Pathophysiology of Parkinson's Disease

Submission Deadline: May 31, 2023

Guest Editor

Dr. Abdelhamid Benazzouz E-Mail

Research Director, Team Leader, Neurochemistry, Deep brain stimulation & Parkinson’s disease, Neurodegenerative Diseases Institute, Bordeaux University, Bordeaux, France

Research Keywords: deep brain stimulation; monoaminergic systems; basal ganglia; animal models

About the Special Issue

Parkinson's disease (PD) is a neurological condition representing the second most common neurodegenerative disorder after Alzheimer's disease. Although the cause of neuronal degeneration is not known, it is accepted that the motor symptoms of PD are due to the degeneration of dopaminergic neurons in the pars compacta of the substantia nigra. In addition, PD is also characterized by the manifestation of non-motor symptoms that may occur even before the motor symptoms and that these disorders may be due to impaired function in the noradrenergic and/or serotonergic system. However, the exact role and mechanisms of involvement of these systems in the pathogenesis and pathophysiology of the disease remain to be determined.
The proposed issue invites papers across, but not limited to, the following themes:
(1) Is there a role of the noradrenergic and/or serotonergic system in the pathophysiology of motor symptoms
(2) Is there a role of the noradrenergic and/or serotonergic system in the pathophysiology of non-motor symptoms
(3) Is there any novel drugs targeting these monoaminergic systems in the treatment of PD
(4) Is there any potential role of noradrenaline in neuroprotection against dopaminergic neurodegeneration
(5) Are the noradrenergic and serotonergic systems involved in the mechanism of L-Dopa-induced dyskinesia in PD

Keywords: Parkinson’s disease; dopamine; noradrenaline; serotonin; cell death; neuroprotection; motor symptoms; non-motor symptoms; risk-factors in PD

Call for Papers

Published Articles

Open Access

Original Article

Aldh1a1 and additional markers of dopamine cell heterogeneity in substantia nigra and ventral tegmental area identified as preserved in two transgenic α-synuclein mouse models of neurodegenerative disease
Aim: Parkinson’s disease (PD) is characterized by degeneration of midbrain dopamine neurons and synucleinopathy [aggregated alpha-synuclein protein (αSyn)]. The correlation between αSyn patho [...] Read more.

Aim:

Parkinson’s disease (PD) is characterized by degeneration of midbrain dopamine neurons and synucleinopathy [aggregated alpha-synuclein protein (αSyn)]. The correlation between αSyn pathology and dopamine neuron degeneration remains to be fully established. Mouse models of PD are commonly used to increase knowledge of disease mechanisms. Lately, midbrain dopamine neurons have gained attention as more heterogeneous than previously recognized. With the aim to determine how the midbrain dopamine system in mice is affected in the presence of αSyn pathology, this brain system was studied in two transgenic mouse models of synucleinopathy.

Methods:

Brain sections from two previously described transgenic mouse lines verified for αSyn pathology through expression of the human αSyn gene (SNCA) under control of the Thy-1 promoter [Thy1-h[A30P]αSyn and Thy1-h[wt]αSyn (L61)], were analyzed using fluorescent in situ hybridization (FISH) and compared with matching sections from wild-type control mice. Probes directed towards mouse and human αSyn mRNA, and a battery of probes towards mRNAs representative of dopamine cell identity and heterogeneity, were implemented.

Results:

First, validation of αSyn-encoding mRNA was performed. Ample ectopic αSyn mRNA was observed throughout the brain of mice of each transgenic line. Next, midbrain dopamine neurons located in substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were analyzed using a battery of general and subpopulation-specific dopamine cell markers. This included tyrosine hydroxylase (Th), vesicular monoamine transporter 2 (Vmat2), dopamine transporter (Dat), aldehyde dehydrogenase 1 family member A1 (Aldh1a1), G-protein-activated inward-rectifying potassium channel type 2 (Girk2), calbindin 1 (Calb1), Calb2, gastrin-releasing peptide (Grp), and vesicular glutamate transporter 2 (Vglut2) mRNAs. No difference between transgenic and control mice was observed for any analyzed marker in either the Thy1-h[A30P]αSyn or Thy1-h[wt]αSyn transgenic mouse line.

Conclusions:

This study demonstrates remarkable robustness of midbrain dopamine cell integrity in the presence of brain-wide ectopic human αSyn in two transgenic mouse models of neurodegenerative disease, motivating further study into mechanisms correlating synucleinopathy with dopamine neuron degeneration in rodent models relevant to PD.

Bianca Vlcek ... Åsa Wallén-Mackenzie

Published: October 30, 2023 Explor Neuroprot Ther. 2023;3:299–327
DOI: https://doi.org/10.37349/ent.2023.00053

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Aim:

Parkinson’s disease (PD) is characterized by degeneration of midbrain dopamine neurons and synucleinopathy [aggregated alpha-synuclein protein (αSyn)]. The correlation between αSyn pathology and dopamine neuron degeneration remains to be fully established. Mouse models of PD are commonly used to increase knowledge of disease mechanisms. Lately, midbrain dopamine neurons have gained attention as more heterogeneous than previously recognized. With the aim to determine how the midbrain dopamine system in mice is affected in the presence of αSyn pathology, this brain system was studied in two transgenic mouse models of synucleinopathy.

Methods:

Brain sections from two previously described transgenic mouse lines verified for αSyn pathology through expression of the human αSyn gene (SNCA) under control of the Thy-1 promoter [Thy1-h[A30P]αSyn and Thy1-h[wt]αSyn (L61)], were analyzed using fluorescent in situ hybridization (FISH) and compared with matching sections from wild-type control mice. Probes directed towards mouse and human αSyn mRNA, and a battery of probes towards mRNAs representative of dopamine cell identity and heterogeneity, were implemented.

Results:

First, validation of αSyn-encoding mRNA was performed. Ample ectopic αSyn mRNA was observed throughout the brain of mice of each transgenic line. Next, midbrain dopamine neurons located in substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were analyzed using a battery of general and subpopulation-specific dopamine cell markers. This included tyrosine hydroxylase (Th), vesicular monoamine transporter 2 (Vmat2), dopamine transporter (Dat), aldehyde dehydrogenase 1 family member A1 (Aldh1a1), G-protein-activated inward-rectifying potassium channel type 2 (Girk2), calbindin 1 (Calb1), Calb2, gastrin-releasing peptide (Grp), and vesicular glutamate transporter 2 (Vglut2) mRNAs. No difference between transgenic and control mice was observed for any analyzed marker in either the Thy1-h[A30P]αSyn or Thy1-h[wt]αSyn transgenic mouse line.

Conclusions:

This study demonstrates remarkable robustness of midbrain dopamine cell integrity in the presence of brain-wide ectopic human αSyn in two transgenic mouse models of neurodegenerative disease, motivating further study into mechanisms correlating synucleinopathy with dopamine neuron degeneration in rodent models relevant to PD.

Open Access

Review

Rehabilitation for non-motor symptoms for patients with Parkinson’s disease from an α-synuclein perspective: a narrative review
Parkinson’s disease (PD) is a common neurodegenerative disorder affecting aged population around the world. PD is characterized by neuronal Lewy bodies present in the substantia nigra of the midbr [...] Read more.

Parkinson’s disease (PD) is a common neurodegenerative disorder affecting aged population around the world. PD is characterized by neuronal Lewy bodies present in the substantia nigra of the midbrain and the loss of dopaminergic neurons with various motor and non-motor symptoms associated with the disease. The protein α-synuclein has been extensively studied for its contribution to PD pathology, as α-synuclein aggregates form the major component of Lewy bodies, a hallmark of PD. In this narrative review, the authors first focus on a brief explanation of α-synuclein aggregation and circumstances under which aggregation can occur, then present a hypothesis for PD pathogenesis in the peripheral nervous system (PNS) and how PD can spread to the central nervous system from the PNS via the transport of α-synuclein aggregates. This article presents arguments both for and against this hypothesis. It also presents various non-pharmacological rehabilitation approaches and management techniques for both motor and non-motor symptoms of PD and the related pathology. This review seeks to examine a possible hypothesis of PD pathogenesis and points to a new research direction focus on rehabilitation therapy for patients with PD. As various non-motor symptoms of PD appear to occur earlier than motor symptoms, more focus on the treatment of non-motor symptoms as well as a better understanding of the biochemical mechanisms behind those non-motor symptoms may lead to better long-term outcomes for patients with PD.

Zhaoyang Liu ... Wen Liu

Published: August 27, 2023 Explor Neuroprot Ther. 2023;3:235–257
DOI: https://doi.org/10.37349/ent.2023.00049

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Parkinson’s disease (PD) is a common neurodegenerative disorder affecting aged population around the world. PD is characterized by neuronal Lewy bodies present in the substantia nigra of the midbrain and the loss of dopaminergic neurons with various motor and non-motor symptoms associated with the disease. The protein α-synuclein has been extensively studied for its contribution to PD pathology, as α-synuclein aggregates form the major component of Lewy bodies, a hallmark of PD. In this narrative review, the authors first focus on a brief explanation of α-synuclein aggregation and circumstances under which aggregation can occur, then present a hypothesis for PD pathogenesis in the peripheral nervous system (PNS) and how PD can spread to the central nervous system from the PNS via the transport of α-synuclein aggregates. This article presents arguments both for and against this hypothesis. It also presents various non-pharmacological rehabilitation approaches and management techniques for both motor and non-motor symptoms of PD and the related pathology. This review seeks to examine a possible hypothesis of PD pathogenesis and points to a new research direction focus on rehabilitation therapy for patients with PD. As various non-motor symptoms of PD appear to occur earlier than motor symptoms, more focus on the treatment of non-motor symptoms as well as a better understanding of the biochemical mechanisms behind those non-motor symptoms may lead to better long-term outcomes for patients with PD.

Guest Editor

About the Special Issue

Call for Papers

Published Articles

Aim:

Methods:

Results:

Conclusions:

Aim:

Methods:

Results:

Conclusions: