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Cells Feb 2023Parkinson's disease (PD) is a multifarious neurodegenerative disease. Its pathology is characterized by a prominent early death of dopaminergic neurons in the pars... (Review)
Review
Parkinson's disease (PD) is a multifarious neurodegenerative disease. Its pathology is characterized by a prominent early death of dopaminergic neurons in the pars compacta of the substantia nigra and the presence of Lewy bodies with aggregated α-synuclein. Although the α-synuclein pathological aggregation and propagation, induced by several factors, is considered one of the most relevant hypotheses, PD pathogenesis is still a matter of debate. Indeed, environmental factors and genetic predisposition play an important role in PD. Mutations associated with a high risk for PD, usually called monogenic PD, underlie 5% to 10% of all PD cases. However, this percentage tends to increase over time because of the continuous identification of new genes associated with PD. The identification of genetic variants that can cause or increase the risk of PD has also given researchers the possibility to explore new personalized therapies. In this narrative review, we discuss the recent advances in the treatment of genetic forms of PD, focusing on different pathophysiologic aspects and ongoing clinical trials.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Neurodegenerative Diseases; Synucleinopathies; Substantia Nigra
PubMed: 36899899
DOI: 10.3390/cells12050764 -
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 -
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 -
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 -
Neural Regeneration Research Mar 2022Parkinson's disease, the second most prevalent neurodegenerative disorder worldwide, is characterized by a progressive loss of dopaminergic neurons in substantia nigra... (Review)
Review
Parkinson's disease, the second most prevalent neurodegenerative disorder worldwide, is characterized by a progressive loss of dopaminergic neurons in substantia nigra pars compacta, causing motor symptoms. This disorder's main hallmark is the formation of intraneuronal protein inclusions, named Lewy bodies and neurites. The major component of these arrangements is α-synuclein, an intrinsically disordered and soluble protein that, in pathological conditions, can form toxic and cell-to-cell transmissible amyloid structures. Preventing α-synuclein aggregation has attracted significant effort in the search for a disease-modifying therapy for Parkinson's disease. Small molecules like SynuClean-D, epigallocatechin gallate, trodusquemine, or anle138b exemplify this therapeutic potential. Here, we describe a subset of compounds containing a single aromatic ring, like dopamine, ZPDm, gallic acid, or entacapone, which act as molecular chaperones against α-synuclein aggregation. The simplicity of their structures contrasts with the complexity of the aggregation process, yet the block efficiently α-synuclein assembly into amyloid fibrils, in many cases, redirecting the reaction towards the formation of non-toxic off-pathway oligomers. Moreover, some of these compounds can disentangle mature α-synuclein amyloid fibrils. Their simple structures allow structure-activity relationship analysis to elucidate the role of different functional groups in the inhibition of α-synuclein aggregation and fibril dismantling, making them informative lead scaffolds for the rational development of efficient drugs.
PubMed: 34380879
DOI: 10.4103/1673-5374.320973 -
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 -
Sensors (Basel, Switzerland) Jan 2022Parkinson's disease (PD) is a neurodegenerative disorder associated with widespread aggregation of α-synuclein and dopaminergic neuronal loss in the substantia nigra...
Parkinson's disease (PD) is a neurodegenerative disorder associated with widespread aggregation of α-synuclein and dopaminergic neuronal loss in the substantia nigra pars compacta. As a result, striatal dopaminergic denervation leads to functional changes in the cortico-basal-ganglia-thalamo-cortical loop, which in turn cause most of the parkinsonian signs and symptoms. Despite tremendous advances in the field in the last two decades, the overall management (i.e., diagnosis and follow-up) of patients with PD remains largely based on clinical procedures. Accordingly, a relevant advance in the field would require the development of innovative biomarkers for PD. Recently, the development of miniaturized electrochemical sensors has opened new opportunities in the clinical management of PD thanks to wearable devices able to detect specific biological molecules from various body fluids. We here first summarize the main wearable electrochemical technologies currently available and their possible use as medical devices. Then, we critically discuss the possible strengths and weaknesses of wearable electrochemical devices in the management of chronic diseases including PD. Finally, we speculate about possible future applications of wearable electrochemical sensors in PD, such as the attractive opportunity for personalized closed-loop therapeutic approaches.
Topics: Biomarkers; Corpus Striatum; Dopamine; Humans; Parkinson Disease; Wearable Electronic Devices
PubMed: 35161694
DOI: 10.3390/s22030951 -
Aging and Disease Jul 2021Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta and other neuronal populations. The worldwide... (Review)
Review
Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta and other neuronal populations. The worldwide prevalence of PD is over 7 million and has been increasing more rapidly than many other neurodegenerative disorders. PD symptoms can be broadly divided into motor (slowness, stiffness, tremor) and non-motor symptoms (such as depression, dementia, psychosis, orthostatic hypotension). Patients can also have prodromal symptoms of rapid eye movement sleep behavior disorder, hyposmia, and constipation. The diagnosis of PD is mainly clinical, but dopamine transporter single-photon emission computed tomography can improve the accuracy of the diagnosis. Dopamine based therapies are used for the treatment of motor symptoms. Non-motor symptoms are treated with other medications such as selective serotonin reuptake inhibitors (depression/anxiety), acetylcholinesterase inhibitors (dementia), and atypical antipsychotics (psychosis). Patients with motor fluctuations or uncontrolled tremor, benefit from deep brain stimulation. Levodopa-carbidopa intestinal gel is an alternative to deep brain stimulation for uncontrolled motor fluctuations. Rehabilitative therapies such as physical, occupational, and speech therapy are important during all stages of the disease. Management of PD is complex but there have been significant advancements in the treatment of motor and non-motor symptoms over the past few years. This review discusses the updates in the medical and surgical management of PD.
PubMed: 34221546
DOI: 10.14336/AD.2020.1225