Parkinson&#39;s Disease

Progressive Loss ◽

Parkinson's disease (PD) is a neurodegenerative disorder in which a progressive loss of the dopaminergic neurons occurs. The loss of the neurons is most prominent in the substantia nigra region of the brain. The prevalence of PD is much greater among the older patients suggesting the risk of PD increases with the increase of age. The exact cause of the neurodegeneration in PD is not known. In this chapter, the authors introduce PD, demonstrate its history, pathogenesis, neurobiology, sign and symptoms, diagnosis, and pharmacotherapy.

Heterogeneity of Incipient Atrophy Patterns in Parkinson’s Disease

10.1101/466086 ◽

2018 ◽

Author(s):

Pedro D. Maia ◽

Sneha Pandya ◽

Justin Torok ◽

Ajay Gupta ◽

Yashar Zeighami ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Neuronal Loss ◽

High Variability ◽

Clinical Value ◽

Optimization Routine ◽

Penalized Optimization ◽

AbstractParkinson’s Disease (PD) is a the second most common neurodegenerative disorder after Alzheimer’s disease and is characterized by cell death in the amygdala and in substructures of the basal ganglia such as the substantia nigra. Since neuronal loss in PD leads to measurable atrophy patterns in the brain, there is clinical value in understanding where exactly the pathology emerges in each patient and how incipient atrophy relates to the future spread of disease. A recent seed-inference algorithm combining an established network-diffusion model with an L1-penalized optimization routine led to new insights regarding the non-stereotypical origins of Alzheimer’s pathologies across individual subjects. Here, we leverage the same technique to PD patients, demonstrating that the high variability in their atrophy patterns also translates into heterogeneous seed locations. Our individualized seeds are significantly more predictive of future atrophy than a single seed placed at the substantia nigra or the amygdala. We also found a clear distinction in seeding patterns between two PD subgroups – one characterized by predominant involvement of brainstem and ventral nuclei, and the other by more widespread frontal and striatal cortices. This might be indicative of two distinct etiological mechanisms operative in PD. Ultimately, our methods demonstrate that the early stages of the disease may exhibit incipient atrophy patterns that are more complex and variable than generally appreciated.

Role of Genes and Treatments for Parkinson’s Disease

The Open Biology Journal ◽

10.2174/1874196702008010047 ◽

2020 ◽

Vol 8 (1) ◽

pp. 47-65

Author(s):

Falaq Naz ◽

Yasir Hasan Siddique

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Autosomal Dominant ◽

Treatment Strategies ◽

Number Of Genes ◽

Permanent Cure

Parkinson’s Disease (PD) is a complex neurodegenerative disorder that mainly results due to the loss of dopaminergic neurons in the substantia nigra of the midbrain. It is well known that dopamine is synthesized in substantia nigra and is transported to the striatum via nigrostriatal tract. Besides the sporadic forms of PD, there are also familial cases of PD and number of genes (both autosomal dominant as well as recessive) are responsible for PD. There is no permanent cure for PD and to date, L-dopa therapy is considered to be the best option besides having dopamine agonists. In the present review, we have described the genes responsible for PD, the role of dopamine, and treatment strategies adopted for controlling the progression of PD in humans.

Association Between Decreased Srpk3 Expression And An Increase In Substantia Nigra Alpha-Synuclein Levels In An MPTP-Induced Parkinson’s Disease Mouse Model

10.21203/rs.3.rs-1207279/v1 ◽

2022 ◽

Author(s):

Min Hyung Seo ◽

Sujung Yeo

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Cell Loss ◽

Alpha Synuclein ◽

Mice Model ◽

Dopaminergic Cell ◽

Abstract Parkinson’s disease (PD) is known as the second most common neurodegenerative disease, which is caused by destruction of dopaminergic neurons in the substantia nigra (SN) of the brain; however, the reason for the death of dopaminergic neurons remains unclear. An increase in α-synuclein (α-syn) is considered an important factor in the pathogenesis of PD. In the current study, we investigated the association between PD and serine/arginine-rich protein specific kinase 3 (Srpk3) in MPTP-induced parkinsonism mice model and in SH-SY5Y cells treated with MPP+. Srpk3 expression was significantly downregulated, while tyrosine hydroxylase (TH) decreased and α-synuclein (α-syn) increased after 4 weeks of MPTP intoxication treatment. Dopaminergic cell reduction and α-syn increase were demonstrated by inhibiting Srpk3 expression by siRNA in SH-SY5Y cells. Moreover, a decrease in Srpk3 expression upon siRNA treatment promoted dopaminergic cell reduction and α-syn increase in SH-SY5Y cells treated with MPP+. These results suggest that the decrease in Srpk3 expression due to Srpk3 siRNA caused both a decrease in TH and an increase in α-syn. This raises new possibilities for studying how Srpk3 controls dopaminergic cells and α-syn expression, which may be related to the pathogenesis of PD. Our results provide an avenue for understanding the role of Srpk3 during dopaminergic cell loss and α-syn increase in the SN. Furthermore, this study could support a therapeutic possibility for PD in that the maintenance of Srpk3 expression inhibited dopaminergic cell reduction.

Drosophila Models of Parkinson's Disease: Discovering Relevant Pathways and Novel Therapeutic Strategies

Parkinson s Disease ◽

10.4061/2011/520640 ◽

2011 ◽

Vol 2011 ◽

pp. 1-14 ◽

Cited By ~ 29

Author(s):

Verónica Muñoz-Soriano ◽

Nuria Paricio

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Model Organism ◽

Disease Process ◽

Therapeutic Strategies ◽

Progressive Loss ◽

Novel Therapeutic Strategies ◽

Drosophila Models

Parkinson's disease (PD) is the second most common neurodegenerative disorder and is mainly characterized by the selective and progressive loss of dopaminergic neurons, accompanied by locomotor defects. Although most PD cases are sporadic, several genes are associated with rare familial forms of the disease. Analyses of their function have provided important insights into the disease process, demonstrating that three types of cellular defects are mainly involved in the formation and/or progression of PD: abnormal protein aggregation, oxidative damage, and mitochondrial dysfunction. These studies have been mainly performed in PD models created in mice, fruit flies, and worms. Among them, Drosophila has emerged as a very valuable model organism in the study of either toxin-induced or genetically linked PD. Indeed, many of the existing fly PD models exhibit key features of the disease and have been instrumental to discover pathways relevant for PD pathogenesis, which could facilitate the development of therapeutic strategies.

Viral vector delivery of neurotrophic factors for Parkinson's disease therapy

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2015.6 ◽

2015 ◽

Vol 17 ◽

Cited By ~ 20

Author(s):

Martin J. Kelly ◽

Gerard W. O'Keeffe ◽

Aideen M. Sullivan

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Clinical Trials ◽

Neurotrophic Factors ◽

Neurotrophic Factor ◽

Dopaminergic Neurons ◽

Viral Vectors ◽

Viral Vector ◽

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the progressive loss of midbrain dopaminergic neurons, which causes motor impairments. Current treatments involve dopamine replacement to address the disease symptoms rather than its cause. Factors that promote the survival of dopaminergic neurons have been proposed as novel therapies for PD. Several dopaminergic neurotrophic factors (NTFs) have been examined for their ability to protect and/or restore degenerating dopaminergic neurons, both in animal models and in clinical trials. These include glial cell line-derived neurotrophic factor, neurturin, cerebral dopamine neurotrophic factor and growth/differentiation factor 5. Delivery of these NTFs via injection or infusion to the brain raises several practical problems. A new delivery approach for NTFs involves the use of recombinant viral vectors to enable long-term expression of these factors in brain cells. Vectors used include those based on adenoviruses, adeno-associated viruses and lentiviruses. Here we review progress to date on the potential of each of these four NTFs as novel therapeutic strategies for PD, as well as the challenges that have arisen, from pre-clinical analysis to clinical trials. We conclude by discussing recently-developed approaches to optimise the delivery of NTF-carrying viral vectors to the brain.

Treating Parkinson’s disease by astrocyte reprogramming: Progress and challenges

Science Advances ◽

10.1126/sciadv.abg3198 ◽

2021 ◽

Vol 7 (26) ◽

pp. eabg3198

Author(s):

Zhuang-Yao D. Wei ◽

Ashok K. Shetty

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Symptomatic Relief ◽

Nonmotor Symptoms ◽

Axonal Projections ◽

Potential Risks

Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder, is typified by both motor and nonmotor symptoms. The current medications provide symptomatic relief but do not stimulate the production of new dopaminergic neurons in the substantia nigra. Astrocyte reprogramming has recently received much attention as an avenue for increasing functional dopaminergic neurons in the mouse PD brain. By targeting a microRNA (miRNA) loop, astrocytes in the mouse brain could be reprogrammed into functional dopaminergic neurons. Such in vivo astrocyte reprogramming in the mouse model of PD has successfully added new dopaminergic neurons to the substantia nigra and increased dopamine levels associated with axonal projections into the striatum. This review deliberates the astrocyte reprogramming methods using specific transcription factors and mRNAs and the progress in generating dopaminergic neurons in vivo. In addition, the translational potential, challenges, and potential risks of astrocyte reprogramming for an enduring alleviation of parkinsonian symptoms are conferred.

α-synuclein−lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson's disease patients

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1821409116 ◽

2019 ◽

Vol 116 (30) ◽

pp. 15226-15235 ◽

Cited By ~ 3

Author(s):

Wojciech Paslawski ◽

Justyna Zareba-Paslawska ◽

Xiaoqun Zhang ◽

Katharina Hölzl ◽

Henrik Wadensten ◽

...

Keyword(s):

Mass Spectrometry ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cerebrospinal Fluid ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Interacting Proteins ◽

Extracellular Milieu ◽

Progressive Accumulation ◽

The progressive accumulation, aggregation, and spread of α-synuclein (αSN) are common hallmarks of Parkinson’s disease (PD) pathology. Moreover, numerous proteins interact with αSN species, influencing its toxicity in the brain. In the present study, we extended analyses of αSN-interacting proteins to cerebrospinal fluid (CSF). Using coimmunoprecipitation, followed by mass spectrometry, we found that αSN colocalize with apolipoproteins on lipoprotein vesicles. We confirmed these interactions using several methods, including the enrichment of lipoproteins with a recombinant αSN, and the subsequent uptake of prepared vesicles by human dopaminergic neuronal-like cells. Further, we report an increased level of ApoE in CSF from early PD patients compared with matched controls in 3 independent cohorts. Moreover, in contrast to controls, we observed the presence of ApoE-positive neuromelanin-containing dopaminergic neurons in substantia nigra of PD patients. In conclusion, the cooccurrence of αSN on lipoprotein vesicles, and their uptake by dopaminergic neurons along with an increase of ApoE in early PD, proposes a mechanism(s) for αSN spreading in the extracellular milieu of PD.

Submicron Crystals of the Parkinson’s Disease Substantia nigra: Calcium Oxalate, Titanium Dioxide and Iron Oxide

10.1101/523878 ◽

2019 ◽

Author(s):

Adam Heller ◽

Sheryl S. Coffman

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Calcium Oxalate ◽

Nlrp3 Inflammasome ◽

Dopaminergic Neurons ◽

Number Density ◽

Neuron Death ◽

Transmission Electron ◽

AbstractParkinson’s disease (PD) results of the death of dopaminergic neurons of the substantia nigra. When activated, the NLRP3 inflammasome of phagocytes releases inflammatory agents, their release resulting in the death of proximal cells. The hallmark protein of PD, aggregated α-synuclein, is phagocytized and activates the NLRP3 inflammasome. Because crystalline particles are known to activate the NLRP3 inflammasome, to enhance α-synuclein expression and aggregation in dopaminergic neurons and because their facets may mis-template adsorbed α-synuclein, we probe here, by transmission electron microscopy (TEM), four human PD substantia nigra specimens for their crystalline particles. Samples weighing 5 mg of PD stages 1, 2, 4 and 5 were processed by proteolysis and centrifugation. TEM-grids were dipped in the centrifugate diluted to 1 mL and the dried films were searched for crystalline particles. Two types of crystalline particles, known to activate the NLRP3 inflammasome were found. Endogenous calcium oxalate, a downstream product of ascorbate and dopamine oxidation-produced hydrogen peroxide; and TiO2, the with pigment of foods and medications. The number-density of the NLRP-inflammasome activating crystalline particles found approached the reported about-equal number-densities of microglia and neuronal cells in the brain.The observations of COD and protein-coated TiO2 support two putative feedback loops, both leading to dopaminergic neuron death. In one, polymeric oxidized-dopamine catalyst accelerates H2O2-generation, the H2O2 indirectly oxidizing ascorbate in an ascorbate-fueled, oxalate-generating, loop the excess oxalate precipitating the subsequently inflammasome-activating COD crystals; In the second, protein-adsorbing facets of TiO2 mis-template the aggregation of α-synuclein to produce inflammasome-activating mis-folded α-synuclein.

Effect of Nebivolol on MPTP Induced Parkinson’s Disease in Mice

International Journal of Pharmaceutical Sciences Review and Research ◽

10.47583/ijpsrr.2021.v69i01.020 ◽

2021 ◽

Vol 69 (1) ◽

Author(s):

Karthigadevi. K ◽

Anbazhagan. S ◽

Jajjara Gopi Sudheer Kumar ◽

Kavimani. S

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Parkinson Disease ◽

Dopaminergic Neurons ◽

Blocking Agent ◽

Protective Effects ◽

The Brain ◽

Anti Inflammation

Parkinson’s disease is the major neurodegenerative disorder, which is due to the loss of dopaminergic neurons in the brain and results in bradykinesia, rigidity, tremor and instable posture. Oxidative stress, Inflammation, Apoptosis has been implicated in the molecular etiopathogenesis of Parkinson disease. In the present study, Nebivolol, a Cardioselective ?-blocking agent which is also reported as an antioxidant, anti-inflammation, anticonvulsant, inhibition of apoptosis and protective effects on gastric ulcer. Hence, nebivolol has been tested for its antiparkinson activity against 1-Methyl, 4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) induced model of Parkinson disease in mice. From this study, the result shown that the nebivolol exerts its beneficial effect against MPTP induced Parkinson’s disease by virtue of its antioxidative, anti-inflammatory and by increases the Dopamine levels in the brain.

Methamphetamine and Parkinson's Disease

Parkinson s Disease ◽

10.1155/2013/308052 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 22

Author(s):

Noelia Granado ◽

Sara Ares-Santos ◽

Rosario Moratalla

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Motor Impairment ◽

Gene Mutations ◽

The Elderly ◽

Epidemiological Studies ◽

Significant Loss

Parkinson's disease (PD) is a neurodegenerative disorder predominantly affecting the elderly. The aetiology of the disease is not known, but age and environmental factors play an important role. Although more than a dozen gene mutations associated with familial forms of Parkinson's disease have been described, fewer than 10% of all cases can be explained by genetic abnormalities. The molecular basis of Parkinson's disease is the loss of dopamine in the basal ganglia (caudate/putamen) due to the degeneration of dopaminergic neurons in the substantia nigra, which leads to the motor impairment characteristic of the disease. Methamphetamine is the second most widely used illicit drug in the world. In rodents, methamphetamine exposure damages dopaminergic neurons in the substantia nigra, resulting in a significant loss of dopamine in the striatum. Biochemical and neuroimaging studies in human methamphetamine users have shown decreased levels of dopamine and dopamine transporter as well as prominent microglial activation in the striatum and other areas of the brain, changes similar to those observed in PD patients. Consistent with these similarities, recent epidemiological studies have shown that methamphetamine users are almost twice as likely as non-users to develop PD, despite the fact that methamphetamine abuse and PD have distinct symptomatic profiles.