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Frontiers in Pharmacology 2023Parkinson's disease (PD) is a common neurodegenerative disorder with motor symptoms, which is caused by the progressive death of dopaminergic (DA) neurons in the... (Review)
Review
Parkinson's disease (PD) is a common neurodegenerative disorder with motor symptoms, which is caused by the progressive death of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Accumulating evidence shows that endoplasmic reticulum (ER) stress occurring in the SNpc DA neurons is an early event in the development of PD. ER stress triggers the activation of unfolded protein response (UPR) to reduce stress and restore ER function. However, excessive and continuous ER stress and UPR exacerbate the risk of DA neuron death through crosstalk with other PD events. Thus, ER stress is considered a promising therapeutic target for the treatment of PD. Various strategies targeting ER stress through the modulation of UPR signaling, the increase of ER's protein folding ability, and the enhancement of protein degradation are developed to alleviate neuronal death in PD models. In this review, we summarize the pathological role of ER stress in PD and update the strategies targeting ER stress to improve ER protein homeostasis and PD-related events.
PubMed: 38026955
DOI: 10.3389/fphar.2023.1288894 -
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 -
Pharmacology, Biochemistry, and Behavior Dec 2020Parkinson's disease (PD) is a progressive neurodegenerative disease with motor and non-motor symptoms. PD is characterized by the degeneration of dopaminergic neurons in... (Review)
Review
Parkinson's disease (PD) is a progressive neurodegenerative disease with motor and non-motor symptoms. PD is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and deficiency of dopamine in the striatal region. The primary objective in PD research is to understand the pathogenesis, targets, and development of therapeutic interventions to control the progress of the disease. The anatomical and physiological resemblances between humans and animals gathered the researcher's attention towards the use of animals in PD research. Due to varying age of onset, symptoms, and progression rate, PD becomes heterogeneous which demands the variety of animal models to study diverse features of the disease. Parkinson is a multifactorial disorder, selection of models become important as not a single model shows all the biochemical features of the disease. Currently, conventional pharmacological, neurotoxin-induced, genetically modified and cellular models are available for PD research, but none of them recapitulate all the biochemical characteristics of the disease. In this review, we included the updated knowledge on the main features of currently available in vivo and in vitro models as well as their strengths and weaknesses.
Topics: Animals; Disease Models, Animal; Dopaminergic Neurons; Humans; Mutation; Parkinson Disease; Substantia Nigra
PubMed: 33091373
DOI: 10.1016/j.pbb.2020.173060 -
CNS & Neurological Disorders Drug... 2022Human Central Nervous System (CNS) is the complex part of the human body, which regulates multiple cellular and molecular events taking place simultaneously. Parkinsons... (Review)
Review
Human Central Nervous System (CNS) is the complex part of the human body, which regulates multiple cellular and molecular events taking place simultaneously. Parkinsons Disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). The pathological hallmarks of PD are loss of dopaminergic neurons in the substantianigra (SN) pars compacta (SNpc) and accumulation of misfolded α-synuclein, in intra-cytoplasmic inclusions called Lewy bodies (LBs). So far, there is no cure for PD, due to the complexities of molecular mechanisms and events taking place during the pathogenesis of PD. Drosophila melanogaster is an appropriate model organism to unravel the pathogenicity not only behind PD but also other NDs. In this context as numerous biological functions are preserved between Drosophila and humans. Apart from sharing 75% of human disease-causing genes homolog in Drosophila, behavioral responses like memory-based tests, negative geotaxis, courtship and mating are also well studied. The genetic, as well as environmental factors, can be studied in Drosophila to understand the geneenvironment interactions behind the disease condition. Through genetic manipulation, mutant flies can be generated harboring human orthologs, which can prove to be an excellent model to understand the effect of the mutant protein on the pathogenicity of NDs.
Topics: Animals; Dopaminergic Neurons; Drosophila melanogaster; Humans; Lewy Bodies; Parkinson Disease; alpha-Synuclein
PubMed: 35040399
DOI: 10.2174/1871527320666210809120621 -
Open Life Sciences 2023The pathogenesis of Parkinson's disease (PD) remains unclear. Among the pathological manifestations is the progressive degeneration of the nigrostriatal dopaminergic... (Review)
Review
The pathogenesis of Parkinson's disease (PD) remains unclear. Among the pathological manifestations is the progressive degeneration of the nigrostriatal dopaminergic pathway, leading to massive loss of neurons in the substantia nigra pars compacta and dopamine (DA) depletion. Therefore, the current drug treatment is primarily based on DA supplementation and delaying the progression of the disease. However, as patients' symptoms continue to worsen, the drug effect will gradually decrease or even disappear, thereby further aggravating clinical symptoms. Gas signaling molecules, such as hydrogen sulfide (HS), nitric oxide (NO), carbon monoxide (CO), and hydrogen (H), exhibit pleiotropic biological functions and play crucial roles in physiological and pathological effects. In common neurodegenerative diseases including Alzheimer's disease and PD, gas signal molecules can prevent or delay disease occurrence via the primary mechanisms of antioxidation, anti-inflammatory response, and antiapoptosis. This article reviews the therapeutic progress of gas signaling molecules in PD models and discusses the possibility of their clinical applications.
PubMed: 37588999
DOI: 10.1515/biol-2022-0658 -
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 -
Neuropeptides Jun 2023Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. The surviving nigral dopaminergic neurons... (Review)
Review
Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. The surviving nigral dopaminergic neurons display altered spontaneous firing activity in Parkinson's disease. The firing rate of nigral dopaminergic neurons decreases long before complete neuronal death and the appearance of parkinsonian symptoms. A mild stimulation could rescue dopaminergic neurons from death and in turn play neuroprotective effects. Several neuropeptides, including cholecystokinin (CCK), ghrelin, neurotensin, orexin, tachykinins and apelin, within the substantia nigra pars compacta play important roles in the modulation of spontaneous firing activity of dopaminergic neurons and therefore involve motor control and motor disorders. Here, we review neuropeptide-induced modulation of the firing properties of nigral dopaminergic neurons. This review may provide a background to guide further investigations into the involvement of neuropeptides in movement control by modulating firing activity of nigral dopaminergic neurons in Parkinson's disease.
Topics: Humans; Dopaminergic Neurons; Parkinson Disease; Neuroprotection; Substantia Nigra; Neuropeptides
PubMed: 37087783
DOI: 10.1016/j.npep.2023.102337 -
Autoimmunity Reviews Dec 2020Parkinson's disease (PD) is a common, age-related, neurodegenerative disorder characterized by motor deficits and a cognitive decline. In the large majority of cases, it... (Review)
Review
Parkinson's disease (PD) is a common, age-related, neurodegenerative disorder characterized by motor deficits and a cognitive decline. In the large majority of cases, it is associated with cytoplasmic aggregation of α-synuclein/SNCA and the formation of Lewy bodies in the dopamine neurons in the substantia nigra pars compacta. The etiopathogenesis of PD remains poorly understood. The disease results from an interplay of genetic and environmental factors, including pharmacological molecules, which destroy dopaminergic neurons. Recently, several notable data have highlighted various immune alterations underlying that PD is associated to autoimmune features and could be considered as an autoimmune disease. In this short article, we briefly review key elements participating to this emerging viewpoint.
Topics: Autoimmune Diseases; Dopaminergic Neurons; Humans; Parkinson Disease; alpha-Synuclein
PubMed: 33131704
DOI: 10.1016/j.autrev.2020.102684 -
Ageing Research Reviews May 2021A number of age-associated neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), possess a... (Review)
Review
A number of age-associated neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), possess a shared characteristic of region-specific neurodegeneration. However, the mechanisms which determine why particular regions within the nervous system are selectively vulnerable to neurodegeneration, whilst others remain relatively unaffected throughout disease progression, remain elusive. Here, we review how regional susceptibility to the ubiquitous physiological phenomenon of normal ageing might underlie the vulnerability of these same regions to neurodegeneration, highlighting three regions archetypally associated with AD, PD and ALS (the hippocampus, substantia nigra pars compacta and ventral spinal cord, respectively), as especially prone to age-related alterations. Placing particular emphasis on these three regions, we comprehensively explore differential regional susceptibility to nervous system tissue, cellular and molecular level ageing to provide an integrated perspective on why age-related neurodegenerative diseases exhibit region-selective vulnerability. Combining these principles with increasingly recognised differences between chronological and biological ageing (termed differential or 'delta' ageing) might ultimately guide therapeutic approaches for these devastating neurodegenerative diseases, for which a paucity of disease modifying and/or life promoting treatments currently exist.
Topics: Aging; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Humans; Parkinson Disease
PubMed: 33639280
DOI: 10.1016/j.arr.2021.101311