Neurodegenerative disorders and the current state, pathophysiology and management of Parkinson’s disease

2021 ◽  
Vol 20 ◽  
Author(s):  
Rahul ◽  
Yasir Siddique
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
General Concept ◽  
Substantia Nigra Pars Compacta ◽  
Protein Accumulation ◽  
Molecular Pathways ◽  
Environmental Toxicants ◽  
Prognostic Accuracy ◽  
Oligomeric Form ◽  
Associated Proteins

: In last few decades major knowledge has been gained about pathophysiological aspects and molecular pathways behind Parkinson’s disease (PD). Based on neurotoxicological studies and postmortem investigations, now there is a general concept that how environmental toxicants (neurotoxins, pesticides insecticides) and genetic factors (genetic mutations in PD-associated proteins) cause depletion of dopamine from substantia nigra pars compacta region of midbrain and modulate cellular processes leading to pathogenesis of PD. α-Synuclein, a neuronal protein accumulation in oligomeric form, called protofibrils is associated with cellular dysfunction and neuronal death thus possibly contributing to PD propagation. With advances made in identifying loci that contribute for PD, molecular pathways involved in disease pathogenesis are now clear and introducing therapeutic strategy at right time may delay the progression. Biomarkers for PD has helped to monitor PD progression, so personalized therapeutic strategies can be facilitated. In order to further improve PD diagnostic and prognostic accuracy, biomarkersfurther large independent validation is required.

scholarly journals Astrocytic Oxidative/Nitrosative Stress Contributes to Parkinson’s Disease Pathogenesis: The Dual Role of Reactive Astrocytes

Antioxidants ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 265 ◽  
Author(s):  
Asha Rizor ◽  
Edward Pajarillo ◽  
James Johnson ◽  
Michael Aschner ◽  
Eunsook Lee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nitrosative Stress ◽  
Critical Role ◽  
Substantia Nigra Pars Compacta ◽  
Environmental Toxicants ◽  
Oxidative And Nitrosative Stress ◽  
Reactive Astrogliosis ◽  
The Impact

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide; it is characterized by dopaminergic neurodegeneration in the substantia nigra pars compacta, but its etiology is not fully understood. Astrocytes, a class of glial cells in the central nervous system (CNS), provide critical structural and metabolic support to neurons, but growing evidence reveals that astrocytic oxidative and nitrosative stress contributes to PD pathogenesis. As astrocytes play a critical role in the production of antioxidants and the detoxification of reactive oxygen and nitrogen species (ROS/RNS), astrocytic oxidative/nitrosative stress has emerged as a critical mediator of the etiology of PD. Cellular stress and inflammation induce reactive astrogliosis, which initiates the production of astrocytic ROS/RNS and may lead to oxidative/nitrosative stress and PD pathogenesis. Although the cause of aberrant reactive astrogliosis is unknown, gene mutations and environmental toxicants may also contribute to astrocytic oxidative/nitrosative stress. In this review, we briefly discuss the physiological functions of astrocytes and the role of astrocytic oxidative/nitrosative stress in PD pathogenesis. Additionally, we examine the impact of PD-related genes such as α-synuclein, protein deglycase DJ-1( DJ-1), Parkin, and PTEN-induced kinase 1 (PINK1) on astrocytic function, and highlight the impact of environmental toxicants, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, manganese, and paraquat, on astrocytic oxidative/nitrosative stress in experimental models.

scholarly journals The cell biology of Parkinson’s disease

2021 ◽  
Vol 220 (4) ◽  
Author(s):  
Nikhil Panicker ◽  
Preston Ge ◽  
Valina L. Dawson ◽  
Ted M. Dawson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Signaling Pathways ◽  
Cell Biology ◽  
Neurodegenerative Disorder ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Cellular Functions ◽  
Neuron Death ◽  
Associated Proteins

Parkinson’s disease (PD) is a progressive neurodegenerative disorder resulting from the death of dopamine neurons in the substantia nigra pars compacta. Our understanding of PD biology has been enriched by the identification of genes involved in its rare, inheritable forms, termed PARK genes. These genes encode proteins including α-syn, LRRK2, VPS35, parkin, PINK1, and DJ1, which can cause monogenetic PD when mutated. Investigating the cellular functions of these proteins has been instrumental in identifying signaling pathways that mediate pathology in PD and neuroprotective mechanisms active during homeostatic and pathological conditions. It is now evident that many PD-associated proteins perform multiple functions in PD-associated signaling pathways in neurons. Furthermore, several PARK proteins contribute to non–cell-autonomous mechanisms of neuron death, such as neuroinflammation. A comprehensive understanding of cell-autonomous and non–cell-autonomous pathways involved in PD is essential for developing therapeutics that may slow or halt its progression.

scholarly journals The Pathopharmacological Interplay between Vanadium and Iron in Parkinson’s Disease Models

2020 ◽  
Vol 21 (18) ◽  
pp. 6719
Author(s):  
Samuel Ohiomokhare ◽  
Francis Olaolorun ◽  
Amany Ladagu ◽  
Funmilayo Olopade ◽  
Melanie-Jayne R. Howes ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Iron Chelation ◽  
Symptomatic Treatment ◽  
Iron Chelator ◽  
Substantia Nigra Pars Compacta ◽  
Motor Deficits ◽  
Environmental Toxicants ◽  
Nigrostriatal Pathway ◽  
Cad Cells

Parkinson’s disease (PD) pathology is characterised by distinct types of cellular defects, notably associated with oxidative damage and mitochondria dysfunction, leading to the selective loss of dopaminergic neurons in the brain’s substantia nigra pars compacta (SNpc). Exposure to some environmental toxicants and heavy metals has been associated with PD pathogenesis. Raised iron levels have also been consistently observed in the nigrostriatal pathway of PD cases. This study explored, for the first time, the effects of an exogenous environmental heavy metal (vanadium) and its interaction with iron, focusing on the subtoxic effects of these metals on PD-like oxidative stress phenotypes in Catecholaminergic a-differentiated (CAD) cells and PTEN-induced kinase 1 (PINK−1)B9Drosophila melanogaster models of PD. We found that undifferentiated CAD cells were more susceptible to vanadium exposure than differentiated cells, and this susceptibility was modulated by iron. In PINK−1 flies, the exposure to chronic low doses of vanadium exacerbated the existing motor deficits, reduced survival, and increased the production of reactive oxygen species (ROS). Both Aloysia citrodora Paláu, a natural iron chelator, and Deferoxamine Mesylate (DFO), a synthetic iron chelator, significantly protected against the PD-like phenotypes in both models. These results favour the case for iron-chelation therapy as a viable option for the symptomatic treatment of PD.

Single-gene mutations in mtDNA-associated proteins are unlikely to be the main cause of sporadic Parkinson's disease. Cumulative genetic variation in numerous genes may be important in neurodegeneration and PD risk

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variation ◽  
Mitochondrial Gene ◽  
Single Gene ◽  
Gene Mutations ◽  
Substantia Nigra Pars Compacta ◽  
Mtdna Mutations ◽  
Age Related ◽  
Associated Proteins

More than two decades ago, numerous individuals with mitochondrial abnormalities and Parkinson's disease were reported. Some of these individuals have mtDNA (mtDNA) mutations, which cause instability. Patients who had neurodegeneration in the SNpc showed that mtDNA abnormalities were important in neurodegeneration and PD risk. Similar findings were found in the MitoPark mice as in PD. Single-gene mutations in mtDNA-associated proteins are unlikely to be the main cause of sporadic PD. The mutation in several genes, functioning in concert in intricate functional networks, results in mild to moderate PD symptoms. Single-gene and PD-GWA studies have had little success in uncovering mtDNA risk loci. In this case, mitochondrial biogenesis and compensation processes are associated with the missing compensatory mechanisms in PD. Maintaining a source of wild-type mtDNA helps to fight age-related development of mtDNA abnormalities. PD risk may be enhanced by increasing age-related neuronal loss, if dysregulated or inhibited.Additionally, PD genes, such as PRKN, LRRK2, are multi-taskers. This involves mtDNA participation as well. Some new discoveries connect mtDNA maintenance and mtDNA stress with PRKN/PINK1 PD-mediated inflammation. mtDNA maintenance pathways might potentially be crucial for monogenic PD. How mitochondria can affect monogenic and sporadic kinds of PD is unknown. Continual study only deepens our understanding of the mitochondrial transcriptome. Additionally, mtDNA is known to encode peptides, mRNAs, and small and long noncoding RNAs. These control mitochondrial gene expression, metabolic activity, and stress response. MtDNA mutations impact the nuclear epigenome through creating variations in mitochondrial intermediates that regulate histones. Additionally, mitochondrial DNA polymerases are present. This creates brand-new possibilities for mtDNA replication and repair. We have identified evidence that nDNA that codes for and/or regulates mitochondrial related activities may add to Parkinson's disease (PD) risk. Cumulative genetic variation in numerous genes (including the NRF-1 and NRF-2 pathway) may be important in neurodegeneration and PD risk. It will need more research to figure out which mtDNA gene mutations are responsible for increasing PD risk.The gradual loss of dopaminergic neurons in the substantia nigra pars compacta is one of the defining characteristics of Parkinson's disease (PD) (SNpc). Rigidity, tremor, and bradykinesia are preceded by hallucinations and sleep difficulties as a result of nigrostriatal dopamine depletion. Symptoms vary greatly and their presence and intensity fluctuate over time. Parkinsonism is a catch-all name for a variety of neurological illnesses, including PD, that can cause symptoms that mimic PD. Parkinsonism instances that lack all of the essential symptoms are referred to as parkinsonism instances.

The mechanistic role of thymoquinone in Parkinson's disease: focus on neuroprotection in pre-clinical studies

2021 ◽  
Vol 14 ◽  
Author(s):  
Mohammad Najim Uddin ◽  
Mohammad Injamul Hoq ◽  
Israt Jahan ◽  
Shafayet Ahmed Siddiqui ◽  
Chayan Dhar Clinton ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Studies ◽  
Nigella Sativa ◽  
Biological Effects ◽  
Neuroprotective Activity ◽  
Substantia Nigra Pars Compacta ◽  
Movement Difficulties

: Thymoquinone (TQ) is one of the leading phytochemicals, which is abundantly found in Nigella sativa L. seeds. TQ exhibited various biological effects such as antioxidant, anti-inflammatory, antimicrobial, and anti-tumoral in several pre-clinical studies. Parkinson's disease (PD) is a long-term neurodegenerative disease with movement difficulties, and the common feature of neurodegeneration in PD patients is caused by dopaminergic neural damage in the substantia nigra pars compacta. The neuroprotective activity of TQ has been studied in various neurological disorders. TQ-mediated neuroprotection against PD yet to be reported in a single frame; therefore, this review is intended to narrate the potentiality of TQ in the therapy of PD. TQ has been shown to protect against neurotoxins via amelioration of neuroinflammation, oxidative stress, apoptosis, thereby protects neurodegeneration in PD models. TQ could be an emerging therapeutic intervention in PD management, but mechanistic studies have been remained to be investigated to clarify its neuroprotective role.

scholarly journals Neuroinflammation in the pathophysiology of Parkinson’s disease and therapeutic evidence of anti-inflammatory drugs

2015 ◽  
Vol 73 (7) ◽  
pp. 616-623 ◽  
Author(s):  
Taysa Bervian Bassani ◽  
Maria A.B.F. Vital ◽  
Laryssa K. Rauh
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Inflammatory Process ◽  
Epidemiological Studies ◽  
Substantia Nigra Pars Compacta ◽  
Fine Motor ◽  
Progressive Degeneration ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting approximately 1.6% of the population over 60 years old. The cardinal motor symptoms are the result of progressive degeneration of substantia nigra pars compacta dopaminergic neurons which are involved in the fine motor control. Currently, there is no cure for this pathology and the cause of the neurodegeneration remains unknown. Several studies suggest the involvement of neuroinflammation in the pathophysiology of PD as well as a protective effect of anti-inflammatory drugs both in animal models and epidemiological studies, although there are controversial reports. In this review, we address evidences of involvement of inflammatory process and possible therapeutic usefulness of anti-inflammatory drugs in PD.

scholarly journals Combined knockout of Lrrk2 and Rab29 does not result in behavioral abnormalities in vivo

2020 ◽  
Author(s):  
Melissa Conti Mazza ◽  
Victoria Nguyen ◽  
Alexandra Beilina ◽  
Jinhui Ding ◽  
Mark R. Cookson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Association Studies ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Genome Wide Association Studies ◽  
Double Knockout ◽  
Knockout Mouse Model

AbstractCoding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson’s disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, leading to the suggestion that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, here we generated a double knockout mouse model and determined whether there are any consequences on brain function with aging. From a battery of motor and non-motor behavioral tests, we noted only that 18-24 month Rab29-/- and double (Lrrk2-/-/Rab29-/-) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in number of substantia nigra pars compacta (SNc) dopamine neurons or in tyrosine hydroxylase levels in the SNc and striatum, which might reflect a PD-like pathology. These results suggest that depletion of both Lrrk2 and Rab29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans.Significance statementGenetic variation in LRRK2 that result in elevated kinase activity can cause Parkinson’s disease (PD), suggesting LRRK2 inhibition as a therapeutic strategy. RAB29, a substrate of LRRK2, has also been associated with increased PD risk. Evidence exists for an interactive relationship between LRRK2 and RAB29. Mouse models lacking either LRRK2 or RAB29 do not show brain pathologies. We hypothesized that the loss of both targets would result in additive effects across in vivo and post-mortem assessments in aging mice. We found that loss of both LRRK2 and RAB29 did not result in significant behavioral deficits or dopamine neuron loss. This evidence suggests that chronic inhibition of this pathway should be tolerated clinically.

scholarly journals Potential Role of Caffeine in the Treatment of Parkinson’s Disease

2016 ◽  
Vol 10 (1) ◽  
pp. 42-58 ◽  
Author(s):  
Mohsin H.K. Roshan ◽  
Amos Tambo ◽  
Nikolai P. Pace
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Randomized Clinical Trials ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Substantia Nigra Pars Compacta ◽  
Muscle Rigidity ◽  
Therapeutic Effects ◽  
Motor Symptoms ◽  
Wide Range

Parkinson’s disease [PD] is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 1% of the population over the age of 55. The underlying neuropathology seen in PD is characterised by progressive loss of dopaminergic neurons in the substantia nigra pars compacta with the presence of Lewy bodies. The Lewy bodies are composed of aggregates of α-synuclein. The motor manifestations of PD include a resting tremor, bradykinesia, and muscle rigidity. Currently there is no cure for PD and motor symptoms are treated with a number of drugs including levodopa [L-dopa]. These drugs do not delay progression of the disease and often provide only temporary relief. Their use is often accompanied by severe adverse effects. Emerging evidence from bothin vivoandin vitrostudies suggests that caffeine may reduce parkinsonian motor symptoms by antagonising the adenosine A2Areceptor, which is predominately expressed in the basal ganglia. It is hypothesised that caffeine may increase the excitatory activity in local areas by inhibiting the astrocytic inflammatory processes but evidence remains inconclusive. In addition, the co-administration of caffeine with currently available PD drugs helps to reduce drug tolerance, suggesting that caffeine may be used as an adjuvant in treating PD. In conclusion, caffeine may have a wide range of therapeutic effects which are yet to be explored, and therefore warrants further investigation in randomized clinical trials.

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