scholarly journals Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease

Science ◽  
2018 ◽  
Vol 362 (6414) ◽  
pp. eaat8407 ◽  
Author(s):  
Tae-In Kam ◽  
Xiaobo Mao ◽  
Hyejin Park ◽  
Shih-Ching Chou ◽  
Senthilkumar S. Karuppagounder ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Parp Inhibitors ◽  
Dopamine Neurons ◽  
Parp Activation ◽  
Disease Modifying Therapy ◽  
Genetic Deletion ◽  
Disease Modifying ◽  
Parp 1

The pathologic accumulation and aggregation of α-synuclein (α-syn) underlies Parkinson’s disease (PD). The molecular mechanisms by which pathologic α-syn causes neurodegeneration in PD are not known. Here, we found that pathologic α-syn activates poly(adenosine 5′-diphosphate–ribose) (PAR) polymerase-1 (PARP-1), and PAR generation accelerates the formation of pathologic α-syn, resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP-1 prevented pathologic α-syn toxicity. In a feed-forward loop, PAR converted pathologic α-syn to a more toxic strain. PAR levels were increased in the cerebrospinal fluid and brains of patients with PD, suggesting that PARP activation plays a role in PD pathogenesis. Thus, strategies aimed at inhibiting PARP-1 activation could hold promise as a disease-modifying therapy to prevent the loss of dopamine neurons in PD.

scholarly journals Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Nolwazi Z. Gcwensa ◽  
Drèson L. Russell ◽  
Rita M. Cowell ◽  
Laura A. Volpicelli-Daley
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Disease Onset ◽  
Neuronal Cell ◽  
Rem Sleep Behavior Disorder ◽  
Dopamine Neurons ◽  
Neuronal Cell Body ◽  
Substantia Nigra Pars Compacta ◽  
Cognitive Changes

Parkinson’s disease (PD) is a progressive neurodegenerative disease that impairs movement as well as causing multiple other symptoms such as autonomic dysfunction, rapid eye movement (REM) sleep behavior disorder, hyposmia, and cognitive changes. Loss of dopamine neurons in the substantia nigra pars compacta (SNc) and loss of dopamine terminals in the striatum contribute to characteristic motor features. Although therapies ease the symptoms of PD, there are no treatments to slow its progression. Accumulating evidence suggests that synaptic impairments and axonal degeneration precede neuronal cell body loss. Early synaptic changes may be a target to prevent disease onset and slow progression. Imaging of PD patients with radioligands, post-mortem pathologic studies in sporadic PD patients, and animal models of PD demonstrate abnormalities in presynaptic terminals as well as postsynaptic dendritic spines. Dopaminergic and excitatory synapses are substantially reduced in PD, and whether other neuronal subtypes show synaptic defects remains relatively unexplored. Genetic studies implicate several genes that play a role at the synapse, providing additional support for synaptic dysfunction in PD. In this review article we: (1) provide evidence for synaptic defects occurring in PD before neuron death; (2) describe the main genes implicated in PD that could contribute to synapse dysfunction; and (3) show correlations between the expression of Snca mRNA and mouse homologs of PD GWAS genes demonstrating selective enrichment of Snca and synaptic genes in dopaminergic, excitatory and cholinergic neurons. Altogether, these findings highlight the need for novel therapeutics targeting the synapse and suggest that future studies should explore the roles for PD-implicated genes across multiple neuron types and circuits.

scholarly journals Traditional Chinese medicine-based neurorestorative therapy for Alzheimer’s and Parkinson’s disease

2019 ◽  
Vol 07 (04) ◽  
pp. 207-222 ◽  
Author(s):  
Zhu Zhang ◽  
Shiqing Zhang ◽  
Cathy Nga-Ping Lui ◽  
Peili Zhu ◽  
Zhang Zhang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Therapeutic Effects ◽  
Alternative Source ◽  
Pharmacological Studies ◽  
Disease Modifying

The prevalence of multiple neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), has been dramatically increasing, particularly in the aging population. However, the currently available therapies merely alleviate the symptoms of these diseases and are unable to retard disease progression significantly. Traditional Chinese medicine (TCM) has been used in clinical practice for thousands of years for ameliorating symptoms or interfering with the pathogenesis of aging- associated diseases. Modern pharmacological studies have proved that TCM imparts disease-modifying therapeutic effects against these diseases, such as protection of neurons, clearance of protein aggregates, and regulation of neuroinflammation. This review summarizes the evidence from recent studies on AD and PD therapies regarding the neuroprotective activities and molecular mechanisms of a series of TCM formulations comprising herbs and their active ingredients. The findings of this review support the use of TCM as an alternative source of therapy for the treatment of neurodegenerative diseases.

scholarly journals The neuroprotective effect of nicotine in Parkinson’s disease models is associated with inhibiting PARP-1 and caspase-3 cleavage

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3933 ◽  
Author(s):  
Justin Y.D. Lu ◽  
Ping Su ◽  
James E.M. Barber ◽  
Joanne E. Nash ◽  
Anh D. Le ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Neuroprotective Effect ◽  
Future Research ◽  
Neuroprotective Effects ◽  
Α7 Nachr ◽  
Parp 1

Clinical evidence points to neuroprotective effects of smoking in Parkinson’s disease (PD), but the molecular mechanisms remain unclear. We investigated the pharmacological pathways involved in these neuroprotective effects, which could provide novel ideas for developing targeted neuroprotective treatments for PD. We used the ETC complex I inhibitor methylpyridinium ion (MPP+) to induce cell death in SH-SY5Y cells as a cellular model for PD and found that nicotine inhibits cell death. Using choline as a nicotinic acetylcholine receptor (nAChR) agonist, we found that nAChR stimulation was sufficient to protect SH-SY5Y cells against cell death from MPP+. Blocking α7 nAChR with methyllycaconitine (MLA) prevented the protective effects of nicotine, demonstrating that these receptors are necessary for the neuroprotective effects of nicotine. The neuroprotective effect of nicotine involves other pathways relevant to PD. Cleaved Poly (ADP-ribose) polymerase-1 (PARP-1) and cleaved caspase-3 were decreased by nicotine in 6-hydroxydopamine (6-OHDA) lesioned mice and in MPP+-treated SH-SY5Y cells. In conclusion, our data indicate that nicotine likely exerts neuroprotective effects in PD through the α7 nAChR and downstream pathways including PARP-1 and caspase-3. This knowledge could be pursued in future research to develop neuroprotective treatments for PD.

scholarly journals Alpha-synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease

2019 ◽  
Author(s):  
Tracy A. Cole ◽  
Hien Zhao ◽  
Timothy J. Collier ◽  
Ivette Sandoval ◽  
Caryl E. Sortwell ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Antisense Oligonucleotides ◽  
Alpha Synuclein ◽  
Nucleotide Polymorphisms ◽  
Gene Encoding ◽  
Disease Modifying Therapy ◽  
Increase Risk ◽  
Disease Modifying

AbstractParkinson’s disease (PD) is a prevalent neurodegenerative disease with no approved disease-modifying therapies. Multiplications, mutations, and single nucleotide polymorphisms in the SNCA gene, encoding alpha-synuclein protein (aSyn), either cause or increase risk for PD. Intracellular accumulations of aSyn are pathological hallmarks of PD. Taken together, reduction of aSyn production may provide a disease-modifying therapy for PD. We show that antisense oligonucleotides (ASOs) reduce production of aSyn in rodent pre-formed fibril (PFF) models of PD. Reduced aSyn production leads to prevention and removal of established aSyn pathology and prevents dopaminergic cell dysfunction. In addition, we address the translational potential of the approach through characterization of human SNCA targeting ASOs that efficiently suppress the human SNCA transcript in vivo. We demonstrate broad activity and distribution of the human SNCA ASOs throughout the non-human primate brain and a corresponding decrease in aSyn cerebral spinal fluid (CSF) levels. Taken together, these data suggest that by inhibiting production of aSyn it may be possible to reverse established pathology and thus supports the development of SNCA ASOs as a potentially disease modifying therapy for PD and related synucleinopathies.SummaryAntisense oligonucleotides designed against SNCA, which are progressing to the clinic, have the potential to be a disease modifying therapeutic for Parkinson’s disease patients.

scholarly journals Biomarker in Parkinson’s Disease: Clinical and Biochemical Biomarker

2021 ◽  
Vol 39 (4) ◽  
pp. 287-297
Author(s):  
Ju-Young Lee ◽  
Hyeo-il Ma ◽  
Young Eun Kim
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disease ◽  
Biological Tissue ◽  
Disease Course ◽  
Prodromal Stage ◽  
Successful Development ◽  
Disease Modifying Therapy ◽  
Clinical Biomarkers ◽  
Disease Modifying

Parkinson’s disease is a neurodegenerative disease compromising progressive motor and non-motor features for a long disease course. Although many drugs controlling parkinsonian symptoms were discovered, treatment with disease-modifying or halting effect was not developed to date. The exploration of reliable biomarkers would be helpful for better predicting disease progression and thereby successful development of disease-modifying therapy. In this review, we will review the clinical biomarkers in the prodromal stage and biomarkers using biological tissue in Parkinson’s disease.

lncRNA NEAT1 prompts autophagy and apoptosis in MPTP-induced Parkinson’s disease by impairing miR-374c-5p

2021 ◽  
Author(s):  
Li Dong ◽  
Yumin Zheng ◽  
Lianbo Gao ◽  
Xiaoguang Luo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Cell Model ◽  
Flow Cytometric Analysis ◽  
Dopamine Neurons ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Brain Disorder ◽  
Lncrna Neat1

Abstract Long non-coding RNAs (lncRNAs) play biological roles in brain disorder and neurodegenerative diseases. As the functions of lncRNA NEAT1 in Parkinson’s disease (PD) remain unknown, in the present study, we aimed to explore the roles and underlying molecular mechanisms of NEAT1 in PD. A PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and a cell model of SH-SY5Y induced by N-methyl-4-phenylpyridinium (MPP+) were established. The ratio of tyrosine hydroxylase (TH+) cells was determined by immunofluorescence assay, and the behavioral changes in mice were observed using pole tests and rotarod tests. The cellular viability and apoptosis of SH-SY5Y were detected by MTT assay and flow cytometric analysis, respectively, and the number of autophagosomes was subsequently measured by transmission electron microscopy. High-performance liquid chromatography was performed to detect the content of dopamine, and a dual-luciferase reporter assay was used to clarify the target of NEAT1 simultaneously. The results demonstrated that the level of NEAT1 was upregulated in the MPTP-induced PD mice, dopamine neurons, and the SH-SY5Y cells treated with MPP+, whereas the level of miR-374c-5p was downregulated. NEAT1 level was positively correlated with MPP+ in a concentration-dependent manner. NEAT1 inhibition efficiently facilitated cell proliferation but inhibited apoptosis and autophagy in the MPP+-treated SH-SY5Y cells. Additionally, silencing of NEAT1 increased the TH+ rate of neurons and suppressed autophagy greatly in PD mice. As a possible target of NEAT1, miR-374c-5p could impact on the apoptosis and autophagy of the SH-SY5Y cells. NEAT1 inhibition upregulated the expression of miR-374c-5p, enhanced SH-SY5Y cell viability, and repressed autophagy and apoptosis in MPTP-induced PD mice. These findings indicated a potential therapeutic role of NEAT1 in treating PD.

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