scholarly journals Triadin Decrease Impairs the Expression of E-C Coupling Related Proteins in Muscles of MPTP-Induced Parkinson’s Disease Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Min Hyung Seo ◽  
Sujung Yeo

Parkinson’s disease (PD), caused by destruction of dopaminergic neurons in the brain, leads to motor symptoms like bradykinesia, tremor, and walking impairments. While most research effort focuses on changes in neuronal pathology we examined how muscle proteins were altered in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. A Ca2+ release channel complex, consisting of ryanodine receptors (RYR), triadin (TRDN), and calsequestrin (CSQ1), is important for excitation-contraction coupling in the sarcoplasmic reticulum membrane in muscles. Thus, we investigated changes in the RYR Ca2+ release channel components in PD mice model. Based on a report that TRDN deletion impairs skeletal muscle function, we also investigated how the knock-down of TRDN affects other components of the RYR channel in the PD model. In this study, the expression levels of the components of RYR channels decreased in the quadriceps femoris muscle of MPTP-induced PD mice and in C2C12 cells treated with 1-methyl-4-phenylpyridinium. We show that decreased TRDN levels decrease RYR and CSQ1 levels. These results suggest that the levels of proteins related to Ca2+ channel function decreased in this model, which could impair muscle function. We conclude that muscle function alterations could add to the bradykinesia and tremor in this model of PD.

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Faith L. Anderson ◽  
Katharine M. von Herrmann ◽  
Angeline S. Andrew ◽  
Yuliya I. Kuras ◽  
Alison L. Young ◽  
...  

AbstractParkinson’s disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms and loss of dopaminergic neurons of the substantia nigra. Inflammation and cell death are recognized aspects of PD suggesting that strategies to monitor and modify these processes may improve the management of the disease. Inflammasomes are pro-inflammatory intracellular pattern recognition complexes that couple these processes. The NLRP3 inflammasome responds to sterile triggers to initiate pro-inflammatory processes characterized by maturation of inflammatory cytokines, cytoplasmic membrane pore formation, vesicular shedding, and if unresolved, pyroptotic cell death. Histologic analysis of tissues from PD patients and individuals with nigral cell loss but no diagnosis of PD identified elevated expression of inflammasome-related proteins and activation-related “speck” formation in degenerating mesencephalic tissues compared with controls. Based on previous reports of circulating inflammasome proteins in patients suffering from heritable syndromes caused by hyper-activation of the NLRP3 inflammasome, we evaluated PD patient plasma for evidence of inflammasome activity. Multiple circulating inflammasome proteins were detected almost exclusively in extracellular vesicles indicative of ongoing inflammasome activation and pyroptosis. Analysis of plasma obtained from a multi-center cohort identified elevated plasma-borne NLRP3 associated with PD status. Our findings are consistent with others indicating inflammasome activity in neurodegenerative disorders. Findings suggest mesencephalic inflammasome protein expression as a histopathologic marker of early-stage nigral degeneration and suggest plasma-borne inflammasome-related proteins as a potentially useful class of biomarkers for patient stratification and the detection and monitoring of inflammation in PD.


2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Jialong Chen ◽  
Kanmin Mao ◽  
Honglin Yu ◽  
Yue Wen ◽  
Hua She ◽  
...  

Abstract Background Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), accompanied by accumulation of α-synuclein, chronic neuroinflammation and autophagy dysfunction. Previous studies suggested that misfolded α-synuclein induces the inflammatory response and autophagy dysfunction in microglial cells. The NLRP3 inflammasome signaling pathway plays a crucial role in the neuroinflammatory process in the central nervous system. However, the relationship between autophagy deficiency and NLRP3 activation induced by α-synuclein accumulation is not well understood. Methods Through immunoblotting, immunocytochemistry, immunofluorescence, flow cytometry, ELISA and behavioral tests, we investigated the role of p38-TFEB-NLRP3 signaling pathways on neuroinflammation in the α-synuclein A53T PD models. Results Our results showed that increased protein levels of NLRP3, ASC, and caspase-1 in the α-synuclein A53T PD models. P38 is activated by overexpression of α-synuclein A53T mutant, which inhibited the master transcriptional activator of autophagy TFEB. And we found that NLRP3 was degraded by chaperone-mediated autophagy (CMA) in microglial cells. Furthermore, p38-TFEB pathways inhibited CMA-mediated NLRP3 degradation in Parkinson's disease. Inhibition of p38 had a protective effect on Parkinson's disease model via suppressing the activation of NLRP3 inflammasome pathway. Moreover, both p38 inhibitor SB203580 and NLRP3 inhibitor MCC950 not only prevented neurodegeneration in vivo, but also alleviated movement impairment in α-synuclein A53T-tg mice model of Parkinson’s disease. Conclusion Our research reveals p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease, which could be a potential therapeutic strategy for PD. Graphical abstract p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease. In this model, p38 activates NLRP3 inflammasome via inhibiting TFEB in microglia. TFEB signaling negatively regulates NLRP3 inflammasome through increasing LAMP2A expression, which binds to NLRP3 and promotes its degradation via chaperone-mediated autophagy (CMA). NLRP3-mediated microglial activation promotes the death of dopaminergic neurons.


2021 ◽  
Vol 12 ◽  
Author(s):  
Babita Singh ◽  
Shivani Pandey ◽  
Mohammad Rumman ◽  
Shashank Kumar ◽  
Prem Prakash Kushwaha ◽  
...  

Ethnopharmacological Relevance: Parkinson’s disease (PD) is characterized by progressive death of dopaminergic neurons. The presently used medicines only tackle the symptoms of PD, but none makes a dent on the processes that underpin the disease’s development. Herbal medicines have attracted considerable attention in recent years. Bacopa monnieri (L.) Wettst (Brahmi) has been used in Indian Ayurvedic medicine to enhance memory and intelligence. Herein, we assessed the neuroprotective role of Bacopa monnieri (L.) Wettst on Parkinson’s disease.Aim of the Study:Bacopa monnieri (L.) Wettst, a medicinal herb, is widely used as a brain tonic. We investigated the neuroprotective and neurorescue properties of Bacopa monnieri (L.) Wettst extract (BME) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of PD.Materials and Methods: The mice model of MPTP-induced PD is used in the study. In the neuroprotective (BME + MPTP) and neurorescue (MPTP + BME) experiments, the animals were administered 40 mg/kg body weight BME orally before and after MPTP administration, respectively. Effect of BME treatment was evaluated by accessing neurobehavioral parameters and levels of dopamine, glutathione, lipid peroxide, and nitrites. An in silico study was performed using AutoDock Tools 1.5.6 (ADT).Results: A significant recovery in behavioral parameters, dopamine level, glutathione level, lipid peroxides, and nitrite level was observed in BME-treated mice. Treatment with BME before or after MPTP administration has a protective effect on dopaminergic neurons, as evidenced by a significant decrease in GFAP immunostaining and expression of inducible nitric oxide synthase (iNOS) in the substantia nigra region; however, the degree of improvement was more prominent in mice receiving BME treatment before MPTP administration. Moreover, the in silico study revealed that the constituents of BM, including bacosides, bacopasides, and bacosaponins, can inactivate the enzyme monoamine oxidase B, thus preventing the breakdown of MPTP to MPP+.Conclusion: Our results showed that BME exerts both neuroprotective and neurorescue effects against MPTP-induced degeneration of the nigrostriatal dopaminergic neurons. Moreover, BME may slow down the disease progression and delay the onset of neurodegeneration in PD.


Author(s):  
Félix Javier Jiménez‐Jiménez ◽  
Hortensia Alonso‐Navarro ◽  
Elena García‐Martín ◽  
José A. G. Agúndez

Diseases ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 24 ◽  
Author(s):  
Neha Joshi ◽  
Atchaya Raveendran ◽  
Shirisha Nagotu

Proper folding to attain a defined three-dimensional structure is a prerequisite for the functionality of a protein. Improper folding that eventually leads to formation of protein aggregates is a hallmark of several neurodegenerative disorders. Loss of protein homeostasis triggered by cellular stress conditions is a major contributing factor for the formation of these toxic aggregates. A conserved class of proteins called chaperones and co-chaperones is implicated in maintaining the cellular protein homeostasis. Expanding the body of evidence highlights the role of chaperones as central mediators in the formation, de-aggregation and degradation of the aggregates. Altered expression and function of chaperones is associated with many neurodegenerative diseases including Parkinson’s disease. Several studies indicate that chaperones are at the center of the cause and effect cycle of this disease. An overview of the various chaperones that are associated with homeostasis of Parkinson’s disease-related proteins and their role in pathogenicity will be discussed in this review.


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