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Frontiers in Neuroscience 2017In vertebrates, dopamine neurons are classically known to modulate locomotion via their ascending projections to the basal ganglia that project to brainstem locomotor... (Review)
Review
In vertebrates, dopamine neurons are classically known to modulate locomotion via their ascending projections to the basal ganglia that project to brainstem locomotor networks. An increased dopaminergic tone is associated with increase in locomotor activity. In pathological conditions where dopamine cells are lost, such as in Parkinson's disease, locomotor deficits are traditionally associated with the reduced ascending dopaminergic input to the basal ganglia. However, a descending dopaminergic pathway originating from the was recently discovered. It innervates the mesencephalic locomotor region (MLR) from basal vertebrates to mammals. This pathway was shown to increase locomotor output in lampreys, and could very well play an important role in mammals. Here, we provide a detailed account on the newly found dopaminergic pathway in lamprey, salamander, rat, monkey, and human. In lampreys and salamanders, dopamine release in the MLR is associated with the activation of reticulospinal neurons that carry the locomotor command to the spinal cord. Dopamine release in the MLR potentiates locomotor movements through a D1-receptor mechanism in lampreys. In rats, stimulation of the elicited dopamine release in the pedunculopontine nucleus, a known part of the MLR. In a monkey model of Parkinson's disease, a reduced dopaminergic innervation of the brainstem locomotor networks was reported. Dopaminergic fibers are also present in human pedunculopontine nucleus. We discuss the conserved locomotor role of this pathway from lamprey to mammals, and the hypothesis that this pathway could play a role in the locomotor deficits reported in Parkinson's disease.
PubMed: 28603482
DOI: 10.3389/fnins.2017.00295 -
Genes & Diseases Jun 2019Parkinson's disease (PD) is the second most common age related neurodegenerative disorder worldwide and presents as a progressive movement disorder. Globally seven... (Review)
Review
Parkinson's disease (PD) is the second most common age related neurodegenerative disorder worldwide and presents as a progressive movement disorder. Globally seven million to 10 million people have Parkinson's disease. Parkinsonism is typically sporadic in nature. Loss of dopaminergic neurons from substantia nigra pars compacta (SNpc) and the neuronal intracellular Lewy body inclusions are the major cause of PD. Gene mutation and protein aggregation play a pivotal role in the degeneration of dopamine neurons. But the actual cause of dopamine degeneration remains unknown. However, several rare familial forms of PD are associated with genetic loci, and the recognition of causal mutations has provided insight into the disease process. Yet, the molecular pathways and gene transformation that trigger neuronal susceptibility are inadequately comprehended. The discovery of a mutation in new genes has provided a basis for much of the ongoing molecular work in the PD field and testing of targeted therapeutics. Single gene mutation in a dominantly or recessively inherited gene results a great impact in the development of Parkinson's disease. In this review, we summarize the molecular genetics of PD.
PubMed: 31193965
DOI: 10.1016/j.gendis.2019.01.004 -
Neuroscience Bulletin Mar 2023The accumulation of pathological α-synuclein (α-syn) in the central nervous system and the progressive loss of dopaminergic neurons in the substantia nigra pars... (Review)
Review
The accumulation of pathological α-synuclein (α-syn) in the central nervous system and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta are the neuropathological features of Parkinson's disease (PD). Recently, the findings of prion-like transmission of α-syn pathology have expanded our understanding of the region-specific distribution of α-syn in PD patients. Accumulating evidence suggests that α-syn aggregates are released from neurons and endocytosed by glial cells, which contributes to the clearance of α-syn. However, the activation of glial cells by α-syn species produces pro-inflammatory factors that decrease the uptake of α-syn aggregates by glial cells and promote the transmission of α-syn between neurons, which promotes the spread of α-syn pathology. In this article, we provide an overview of current knowledge on the role of glia and α-syn pathology in PD pathogenesis, highlighting the relationships between glial responses and the spread of α-syn pathology.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Dopaminergic Neurons; Pars Compacta
PubMed: 36229715
DOI: 10.1007/s12264-022-00957-z -
Neurosciences (Riyadh, Saudi Arabia) Jan 2024Parkinson's disease (PD) is a complex neurodegenerative motor disorder caused by the loss of dopaminergic neurons in the substantia nigra pars compacta. The substantia... (Review)
Review
Parkinson's disease (PD) is a complex neurodegenerative motor disorder caused by the loss of dopaminergic neurons in the substantia nigra pars compacta. The substantia nigra is neither the first nor the only brain region affected by PD. Recent and old studies have shown that PD does not only affect the CNS; in fact, autonomic innervation in the GIT, skin, and olfactory system was found to be affected by α-synuclein pathology outside the CNS, affecting patients' quality of life. In the gastrointestinal system, dysphagia, constipation, and bacterial overgrowth in the small intestine are common in patients with PD. In addition, several skin conditions were reported in PD, including seborrheic dermatitis, rosacea, melanoma, and others. Finally, olfactory system dysfunction, such as reduced touch sensation and smell, was associated with motor abnormalities. Further high-quality studies are needed to develop reliable tests that could help in the early diagnosis of PD.
Topics: Humans; Parkinson Disease; Quality of Life; Smell; Skin Abnormalities
PubMed: 38195133
DOI: 10.17712/nsj.2024.1.20230062 -
Behavioural Brain Research Feb 2024Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and the presence of Lewy bodies (LBs) or Lewy neurites (LNs) which consist of α-synuclein (α-syn) and a complex mix of other biomolecules. Mitochondrial dysfunction is widely believed to play an essential role in the pathogenesis of PD and other related neurodegenerative diseases. But mitochondrial dysfunction is subject to complex genetic regulation. There is increasing evidence that PD-related genes directly or indirectly affect mitochondrial integrity. Therefore, targeted regulation of mitochondrial function has great clinical application prospects in the treatment of PD. However, lots of PD drugs targeting mitochondria have been developed but their clinical therapeutic effects are not ideal. This review aims to reveal the role of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases based on the mitochondrial structure and function, which may highlight potential interventions and therapeutic targets for the development of PD drugs to recover mitochondrial dysfunction in neurodegenerative diseases.
Topics: Humans; Parkinson Disease; Neurodegenerative Diseases; alpha-Synuclein; Pars Compacta; Mitochondria; Dopaminergic Neurons; Mitochondrial Diseases
PubMed: 38103871
DOI: 10.1016/j.bbr.2023.114811 -
Frontiers in Aging Neuroscience 2018It has been 200 years since Parkinson disease (PD) was described by Dr. Parkinson in 1817. The disease is the second most common neurodegenerative disease characterized... (Review)
Review
It has been 200 years since Parkinson disease (PD) was described by Dr. Parkinson in 1817. The disease is the second most common neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although the pathogenesis of PD is still unknown, the research findings from scientists are conducive to understand the pathological mechanisms. It is well accepted that both genetic and environmental factors contribute to the onset of PD. In this review, we summarize the mutations of main seven genes (α-synuclein, LRRK2, PINK1, Parkin, DJ-1, VPS35 and GBA1) linked to PD, discuss the potential mechanisms for the loss of dopaminergic neurons (dopamine metabolism, mitochondrial dysfunction, endoplasmic reticulum stress, impaired autophagy, and deregulation of immunity) in PD, and expect the development direction for treatment of PD.
PubMed: 29719505
DOI: 10.3389/fnagi.2018.00109 -
Neurobiology of Aging Mar 2023Currently, little is known about the impact of aging on astrocytes in substantia nigra pars compacta (SNpc), where dopaminergic neurons degenerate both in physiological...
Currently, little is known about the impact of aging on astrocytes in substantia nigra pars compacta (SNpc), where dopaminergic neurons degenerate both in physiological aging and in Parkinson's disease, an age-related neurodegenerative disorder. We performed a morphometric analysis of GFAP astrocytes in SNpc and, for comparison, in the pars reticulata (SNpr) of young (4-6 months), middle-aged (14-17 months) and old (20-24 months) C57BL/6J male mice. We demonstrated an age-dependent increase of structural complexity only in astrocytes localized in SNpc, and not in SNpr. Astrocytic structural remodelling was not accompanied by changes in GFAP expression, while GFAP increased in SNpr of old compared to young mice. In parallel, transcript levels of selected astrocyte-enriched genes were evaluated. With aging, decreased GLT1 expression occurred only in SNpc, while xCT transcript increased both in SNpc and SNpr, suggesting a potential loss of homeostatic control of extracellular glutamate only in the subregion where age-dependent neurodegeneration occurs. Altogether, our results support an heterogenous morphological and biomolecular response to aging of GFAP astrocytes in SNpc and SNpr.
Topics: Mice; Male; Animals; Pars Compacta; Substantia Nigra; Pars Reticulata; Astrocytes; Mice, Inbred C57BL; Aging
PubMed: 36630756
DOI: 10.1016/j.neurobiolaging.2022.12.010 -
International Journal of Molecular... Mar 2021Parkinson's disease is one of the most common neurodegenerative disorders worldwide, characterized by a progressive loss of dopaminergic neurons mainly localized in the... (Review)
Review
Parkinson's disease is one of the most common neurodegenerative disorders worldwide, characterized by a progressive loss of dopaminergic neurons mainly localized in the . In recent years, the detailed analyses of both genetic and idiopathic forms of the disease have led to a better understanding of the molecular and cellular pathways involved in PD, pointing to the centrality of mitochondrial dysfunctions in the pathogenic process. Failure of mitochondrial quality control is now considered a hallmark of the disease. The peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) family acts as a master regulator of mitochondrial biogenesis. Therefore, keeping PGC-1 level in a proper range is fundamental to guarantee functional neurons. Here we review the major findings that tightly bond PD and PGC-1s, raising important points that might lead to future investigations.
Topics: Animals; DNA, Mitochondrial; DNA-Binding Proteins; Dopaminergic Neurons; Genome-Wide Association Study; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mice; Mitochondria; Neurodegenerative Diseases; Neurons; Organelle Biogenesis; Oxidative Stress; Parkinson Disease; Pars Compacta; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Protein Deglycase DJ-1; Protein Kinases; Transcription Factors; Ubiquitin-Protein Ligases; Vesicular Transport Proteins; alpha-Synuclein
PubMed: 33800548
DOI: 10.3390/ijms22073487 -
The British Journal of Radiology Jul 2022Parkinson's disease is a neurodegenerative disorder caused by neuronal cell loss in the substantia nigra pars compacta (SNpc). We aimed to perform atlas-based...
OBJECTIVE
Parkinson's disease is a neurodegenerative disorder caused by neuronal cell loss in the substantia nigra pars compacta (SNpc). We aimed to perform atlas-based relaxometry using an anatomical SNpc atlas and obtain baseline values of SNpc regions in healthy volunteers.
METHODS
Neuromelanin (NM)-sensitive imaging of the midbrain and whole-brain 3D weighted images of 27 healthy volunteers (20 males; aged 36.3 ± 11.5 years) were obtained. An anatomical SNpc atlas was created using NM-sensitive images in standard space, and divided into medial (MG), dorsal (DG), and ventrolateral (VG) groups. Proton density (PD), T, and T values in these regions were obtained using quantitative MRI. The relationships between PD, T, and T values in each SNpc region and age were evaluated.
RESULTS
The VG PD value was significantly higher than the MG and DG values. MG, DG, and VG T values were significantly different, whereas the T value of the MG was significantly lower than the DG and VG values. Moreover, a significant negative correlation between PD and T values of the MG and age was observed.
CONCLUSION
The PD, T, and T values of the SNpc regions measured in standard space using an anatomical atlas can be used as baseline values. PD and T values of the SNpc regions may be associated with NM concentrations.
ADVANCES IN KNOWLEDGE
An anatomical SNpc atlas was created using NM-sensitive MRI and can be used for the quantitative evaluation of subsegments of the SNpc in standard space.
Topics: Healthy Volunteers; Humans; Magnetic Resonance Imaging; Male; Parkinson Disease; Pars Compacta; Protons; Substantia Nigra
PubMed: 35357890
DOI: 10.1259/bjr.20210572 -
Aging Jun 2022The ventral tegmental area (VTA), substantia nigra pars compacta (SNpc) and nucleus accumbens (NAc) are involved in the regulation of appetite and motivational...
The effects of ninjin'yoeito on the electrophysiological properties of dopamine neurons in the ventral tegmental area/substantia nigra pars compacta and medium spiny neurons in the nucleus accumbens.
The ventral tegmental area (VTA), substantia nigra pars compacta (SNpc) and nucleus accumbens (NAc) are involved in the regulation of appetite and motivational behaviors. A traditional Japanese (Kampo) medicine, ninjin'yoeito (NYT), has been reported to improve decreased motivation and anorexia in patients with Alzheimer's disease and apathy-like model mice. Thus, NYT may affect the activities of neurons in the VTA, SNpc and NAc. However, little is known about the underlying mechanisms of NYT. Here, we investigated the effects of NYT on the electrophysiological properties of dopaminergic neurons in the VTA and SNpc, as well as on those of medium spiny neurons (MSNs) in the NAc (core and shell subregions), by applying the patch-clamp technique in the brain slices. NYT reduced the resting membrane potential of VTA and SNpc dopaminergic neurons. In contrast, NYT increased the firing frequency of NAc MSNs accompanied by shortened first spike latency and interspike interval. Furthermore, NYT attenuated the inward rectification and sustained outward currents. In conclusion, NYT may directly influence the excitability of dopaminergic neurons in the VTA and SNpc, as well as MSNs in the NAc (core and shell). NYT may modulate dopamine signals in appetite and motivational behaviors.
Topics: Animals; Dopaminergic Neurons; Drugs, Chinese Herbal; Humans; Mice; Nucleus Accumbens; Pars Compacta; Ventral Tegmental Area
PubMed: 35660668
DOI: 10.18632/aging.204109