CDK5-USP30 signaling pathway regulates MAVS-mediated inflammation via suppressing mitophagy in MPTP/MPP+ PD model.

The discovery of MPTP, an industrial chemical and contaminant of illicit narcotics, which causes parkinsonism in humans, non-human primates and rodents, has led to environmental pollutants exposure being convicted as key candidate in Parkinson's disease (PD) pathogenesis. Though MPTP-induced mitochondrial dysfunction and neuroinflammation are mainly responsible for the causative issue of MPTP neurotoxicity, the underlying mechanism involved remains unclear. Here, we reveal a novel signaling mechanism of CDK5-USP30-MAVS regulating MPTP/MPP+ induced PD. MPP+ (the toxic metabolite of MPTP) treatment not only led to the increased protein levels of USP30 but also to mitophagy inhibition, mitochondrial dysfunction, and MAVS-mediated inflammation in BV2 microglial cells. Both mitophagy stimulation (Urolithin A administration) and USP30 knockdown relieved MAVS-mediated inflammation via restoring mitophagy and mitochondrial function in MPP+-induced cell model. Notably, MPTP/MPP+-induced CDK5 activation regulated USP30 phosphorylation at serine 216 to stabilize USP30. Moreover, CDK5-USP30 pathway promoted MAVS-mediated inflammation in MPTP/MPP+-induced PD model. Inhibition of CDK5 not only had a protective effect on MPP+-induced cell model of PD via suppressing the upregulation of USP30 and the activation of MAVS inflammation pathway in vitro, but also prevented neurodegeneration in vivo and alleviated movement impairment in MPTP mouse model of PD. Overall, our study reveal that CDK5 blocks mitophagy through phosphorylating USP30 and activates MAVS inflammation pathway in MPTP/MPP+-induced PD model, which suggests that CDK5-USP30-MAVS signaling pathway represents a valuable treatment strategy for PD induced by environmental neurotoxic pollutants in relation to MPTP.

Global burden and trends of three common road injuries from 1990 to 2019 and the implications for prevention and intervention.

BACKGROUND: Analysis on the burden of specific types of road injuries (RIs) in the previous Global burden of disease (GBD) studies is lacking. The present work aimed to analyze the burden of three common RIs using the updated data of the GBD 2019, which would inform policy-making. METHODS: Data on cyclist road injuries (CRIs), motorcyclist road injuries (MRIs), and motor vehicle road injuries (MVRIs) were extracted from the GBD 2019. Trends of age-standardized rate (ASR) were predicted using estimated annual percentage change (EAPC) from 1990 to 2019. RESULTS: Over the past three decades, the global incident ASRs of CRIs and MRIs presented increasing trends, but that of MVRIs declined slightly. However, trends of death and disability adjusted life years (DALYs) caused by three common RIs decreased in most regions and countries. Particularly, trends in ASRs of years of life lost (YLLs) cuased by RIs decreased more pronouncedly than that of years of life lived with disability (YLDs). The burden of three common RIs showed significant social and demographic characteristics. Low-middle and middle socio-demographic index (SDI) areas had a heavy burden of RIs, particularly CRIs and MRIs. However, the high SDI area undertook a relatively low burden, and presented more pronounced downward trends in death and DALYs. CONCLUSIONS: The burden and changing trends of three common RIs were geographically heterogeneous. The findings highlighted that increasing incident trends of RIs needed more cost-effective measures of prevention and intervention.

Global, regional, and national burden of asbestosis from 1990 to 2019 and the implications for prevention and control.

BACKGROUND: Asbestosis is a common pneumoconiosis caused by long-term asbestos exposure. Analysis of the burden of asbestosis would help in creating informed public health strategies. METHODS: Data on asbestosis were analyzed using the Global Burden of Disease study 2019. The estimated annual percentage change (EAPC) was calculated to demonstrate temporal trends in the age-standardized rate (ASR) of asbestosis from 1990 to 2019. RESULTS: Globally, 36,339 incident cases of asbestosis, led to 3572 deaths and 71,225 disability adjusted life years (DALYs) in 2019. During 1990-2019, the overall ASRs of incidence and DALYs declined by an annual average of 0.29 % and 0.27 %, with the respective EAPCs being -0.29 (95 % confidence interval [CI]: -0.43, -0.14) and -0.27 (95%CI: -0.53, -0.01). The ASRs of mortality increased with EAPC of 0.65 (95%CI: 0.34, 0.96). Trends in incidence and prevalence rose in females, but declined in males. The asbestosis burden was heterogeneous across regions and countries. The heaviest burden of asbestosis was observed in the United States, India, and China. Trends in ASRs of asbestosis varied across countries/territories. Pronounced increasing trends in incidence and prevalence occurred in Georgia, Iran, and Croatia. CONCLUSIONS: Decreasing incident trend of asbestosis was observed globally over the past three decades. However, the ongoing asbestosis burden highlighted that asbestosis remained a challenge to public health, and cost-effective measures were required to reduce the asbestosis burden.

Global burden and trends of firearm violence in 204 countries/territories from 1990 to 2019.

Background: Gaps remained in the updated information of the firearm violence (FV) burden from a global landscape. Understanding the global burden of FV could contribute to decision-making. Methods: Data on the FV burden, including physical violence by firearm (PVF), self-harm by firearm (SHF), and unintentional firearm injuries (UFI), were extracted from the Global Burden of Disease 2019. The temporal trends of age-standardized rate (ASR) were estimated using estimated annual percentage change (EAPC). Results: In 2019, PVF, SHF, and UFI reported 710.64 × 103, 335.25 × 103, and 2,133.88 × 103, respectively, incident cases worldwide. Their ASR (/100,000 people-years) were 9.31, 4.05, and 28.07. During 1990-2019, the overall incident ASRs of PVF presented an increasing trend (EAPC = 0.61, 95% confidence interval [CI]: 0.48 to 0.75). Notably, pronounced increasing trends were observed in Tropical Latin America, and North Africa and Middle East. However, incident trends of SHF and UFI declined globally, with the respective EAPCs being -0.68 (95% CI: -0.83 to -0.54) and -0.98 (95% CI: -1.19 to -0.77). In 2019, the ASR of death due to PVF, SHF, and UFI were 2.23, 0.65, and 0.26, and that of DALYs were 127.56, 28.10, and 17.64, respectively. Decreasing trends in the ASRs of FV were observed in most regions and countries worldwide over the past three decades, particularly that of PVF in Estonia. Conclusion: The FV burden was heterogeneous across regions and countries, which was deeply subjected to socioeconomic factors. The findings highlighted that specific prevention strategies and interventions were required, particularly in the high prevalent settings.

Global Trends in Death, Years of Life Lost, and Years Lived With Disability Caused by Breast Cancer Attributable to Secondhand Smoke From 1990 to 2019.

Background: Secondhand smoke is an important risk factor to breast cancer patients' survival. This article aimed to describe the epidemiological changes of health loss caused by female breast cancer attributable to secondhand smoke from 1990 to 2019. Methods: Data on breast cancer was derived from the Global Burden of Disease study 2019. The epidemiological status and trends were estimated using the number, age-standardized rate (ASR), and estimated annual percentage change (EAPC). Results: In 2019, secondhand smoke-related breast cancer caused 168.33×102 death, 5242.58×102 years of life lost (YLLs), and 334.03×102 years lived with disability (YLDs) globally. The overall ASR of death and YLLs caused by breast cancer attributable to secondhand smoke presented decreasing trends from 1990 to 2019, with the respective EAPCs of -0.78 and -0.87. Meanwhile, decreasing trends occurred in most geographic regions, particularly that of YLLs in high-income North America (EAPC = -3.35). At the national level, most countries/territories had decreasing trends of death and YLLs, particularly Denmark, in which the respective EAPCs were -4.26 and -4.64. However, the ASR of YLDs showed an increasing trend globally (EAPC = 0.32). Meanwhile, increasing trends were observed in most regions and countries, particularly the Solomon Islands and Lesotho, with the respective EAPCs being 6.18 and 4.33. The changing trends were closely associated with sociodemographic development. Conclusions: Trends in secondhand smoke-related death and YLLs caused by breast cancer declined from 1990 to 2019. However, secondhand smoke remains a challenge to the patients' longevity and quality of life. The findings informed strategies should be strengthened the control of secondhand smoking.

Deacetylation of ZKSCAN3 by SIRT1 induces autophagy and protects SN4741 cells against MPP+-induced oxidative stress.

Mitochondrial dysfunction, oxidative stress and misfolded protein aggregation are related to autophagy-lysosomal dysregulation and contribute to the pathogenesis of Parkinson' s disease (PD). ZKSCAN3, a transcriptional repressor, plays a crucial role in autophagy and lysosomal biogenesis. However, the role and modification of ZKSCAN3 in the defection of ALP, along with the molecular mechanism involved in pathogenesis of PD, still remain unclear. In this study, we demonstrated that cellular reactive oxygen species (ROS) generated by MPP+ exposure and the resulting oxidative damage were counteracted by SIRT1-ZKSCAN3 pathway induction. Here we showed that nuclear ZKSCAN3 significantly increased in ventral midbrain of MPTP-treated mice and MPP+-treated SN4741 cells. Knockdown of ZKSCAN3 alleviated MPP+-induced ALP defect, Tyrosine Hydroxylase (TH) declination and neuronal death. NAC, a ROS scavenger, reduced the nuclear translocation of ZKSCAN3 and sequentially improved ALP function in MPP+-treated SN4741 cells. SRT2104, a SIRT1 activator, attenuated impairment of ALP in MPP+-treated SN47417 cells through decreasing nuclear accumulation of ZKSCAN3 and protected dopaminergic neurons from MPTP injury. Moreover, SRT2104 relieved impairment in locomotor activities and coordination skills upon treatment of MPTP in C57/BL6J mice through behavior tests including rotarod, pole climbing and grid. Furthermore, ZKSCAN3 was a novel substrate of SIRT1 which was deacetylated at lysine 148 residues by SIRT1. This subsequently facilitated the shuttling of ZKSCAN3 to the cytoplasm. Therefore, our study identifies a novel acetylation-dependent regulatory mechanism of nuclear translocation of ZKSCAN3. It results in autophagy-lysosomal dysfunction and then leads to DA neuronal death in MPTP/MPP+ model of PD.

Poly (ADP-ribose) polymerase 1 inhibition prevents neurodegeneration and promotes α-synuclein degradation via transcription factor EB-dependent autophagy in mutant α-synucleinA53T model of Parkinson's disease.

Poly (ADP-ribose) polymerase 1 (PARP1) is a master regulator of diverse biological processes such as DNA repair, oxidative stress, and apoptosis. PARP1 can be activated by aggregated α-synuclein, and this process in turn exacerbates toxicity of α-synuclein. This circle is closely linked to the evolution of Parkinson's disease (PD) that characterized by progressive neurodegeneration and motor deficits. Here, we reported the PARP1, as a novel upstream molecular of transcription factor EB (TFEB), participates in regulation of autophagy in α-synuclein aggregated cells and mice. PARP1 inhibition not only enhances the nuclear transcription of TFEB via SIRT1 mediated down-regulation of mTOR signaling but also reduces nuclear export of TFEB by attenuating the TFEB-CRM1 interaction. Our results revealed that PARP1 inhibition lessened the accumulation of α-synuclein in PD models. Also, oral administration of PARP1 inhibitor Veliparib prevented neurodegeneration and improved motor ability in α-synucleinA53T transgenic mice. These findings identify that PARP1 signaling pathway regulates TFEB-mediated autophagy, pointing to potential therapeutic strategy of PD via enhancing protein degradation systems.

p38 MAPK-DRP1 signaling is involved in mitochondrial dysfunction and cell death in mutant A53T α-synuclein model of Parkinson's disease.

Abnormal accumulation of α-synuclein and mitochondria dynamics dysfunction are considered to be implicated in the pathogenesis of Parkinson's disease. However, the underlying mechanisms how α-synuclein abnormal accumulation causes mitochondrial dynamics dysfunction remains unclear. Here, we demonstrate that dynamin-related protein 1(DRP1) is a substrate for p38 MAPK, mutant α-synuclein overexpression in SN4741 cell caused p38 MAPK activation, p38 MAPK-mediated phosphorylation DRP1 at serine 616 to activate DRP1 and is associated with increased mitochondrial fission, which resulted in mitochondrial dysfunction and neuronal loss. Inhibition of p38 MAPK or expression of a kinase death form of p38 MAPK not only attenuates DRP1-mediated mitochondrial fission，but also restores the mitochondrial dysfunction and cell death in α-synuclein A53T model. These findings showed that inhibition of p38 MAPK-DRP1 signaling pathway may be a viable therapeutic strategy of PD on maintenance of mitochondrial homeostasis.

Mitochondrial calcium dysfunction contributes to autophagic cell death induced by MPP+ via AMPK pathway.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra. Prevailing evidence suggests that abnormal autophagy and mitochondrial dysfunction participate in the process of PD. However, many damages of neuronal functions are regulated by intracellular Ca2+ signaling and the contribution of mitochondrial Ca2+ to the process of neurodegeneration is still unclear. MPP+, the metabolite of a neurotoxin MPTP, causes symptom of PD in animal models by selectively destroying dopaminergic neurons in substantia nigra. Here we report that mitochondrial Ca2+ uniporter (MCU) participated in MPP+-induced autophagic cell death in SH-SY5Y cells. Pharmacological agonist of MCU or exogenous expressed MCU can partially reduce MPP+-induced autophagic cell death. Down-regulation of MCU enhanced autophagic cell death via AMPK activation, which was independent of Beclin1 and PI3K. These findings show that the mitochondrial calcium dyshomeostasis contributes to MPP+-induced neuronal degeneration, and MCU may be a potential therapeutic target of PD through the prevention of pathological autophagy.

Role of c-Abl-GSK3ß Signaling in MPP+-Induced Autophagy-Lysosomal Dysfunction.

Impairment in autophagy-lysosomal pathway (ALP) results in accumulation of misfolded proteins and dysfunctional organelles, which is the hallmark of neurodegenerative diseases including Parkinson's disease (PD). Recent studies revealed activated nonreceptor tyrosine kinase Abelson (c-Abl) in PD models and brain specimen of PD patients. Inhibition of c-Abl through pharmacological inhibitors has been shown to enhance ALP function and provide neuroprotective effects in cells and animal models of PD. However, the molecular mechanisms of neuroprotective effects underlying c-Abl inhibition remain elusive. In this study, STI-571, a c-Abl inhibitor, rescued the ALP function through facilitating the nuclear translocation of TFEB and protected against MPP+-induced neuronal cell death. Furthermore, siRNA-mediated knock-down or pharmacological inhibition of GSK3ß mitigated the MPP+-induced neuronal cell death, which was achieved through promoting TFEB nuclear localization and subsequently reversing the function of ALP. Intriguingly, either DPH, c-Abl activator, or MPP+ led to the activation of GSK3ß, which is a negative regulator of TFEB. In addition, c-Abl directly interacted with GSK3ß and catalyzed its phosphorylation at tyrosine 216, and their interaction was enhanced under MPP+ treatment. In contrast, STI-571 abrogated phosphorylation of GSK3ß-Tyr216 induced by MPP+ in SN4741 cells and in primary midbrain neurons. Taken together, these results demonstrate that GSK3ß is a novel c-Abl substrate, and c-Abl-GSk3ß pathway mediates MPP+-induced ALP defects and neuronal cell death, which may represent a potential therapeutic target for PD.

Phosphorylation of Parkin at serine 131 by p38 MAPK promotes mitochondrial dysfunction and neuronal death in mutant A53T α-synuclein model of Parkinson's disease.

α-synuclein abnormal accumulation and mitochondria dysfunction are involved in the pathogenesis of Parkinson's disease. Selective autophagy of mitochondria (mitophagy) is a crucial component of the network controlling the mitochondrial homeostasis. However, the underlying mechanism that mutant α-synuclein induces mitochondrial abnormality through mitophagy impairment is not fully understood. Here, we showed that mutant A53T α-synuclein accumulation impaired mitochondrial function and Parkin-mediated mitophgy in α-synucleinA53T model. α-synucleinA53T overexpression caused p38 MAPK activation, then p38 MAPK directly phosphorylated Parkin at serine 131 to disrupt the Parkin's protective function. The p38 MAPK inhibition significantly reduced cellular apoptosis, restored mitochondrial membrane potential as well as increased synaptic density both in SN4741 cells and primary midbrain neurons. These findings show that the p38 MAPK-Parkin signaling pathway regulates mitochondrial homeostasis and neuronal degeneration, which may be a potential therapeutic strategy of PD via enhancing mitochondrial turn-over and maintenance.

Mitochondrial calcium uniporter-mediated inhibition of 1-methyl-4-phenylpyridinium ions neurotoxicity in PC12 cells.

Parkinson's disease (PD) is one of the most debilitating neurodegenerative disorders. The etiology of sporadic PD remains unknown. One prominent hypothesis is that impaired mitochondrial function may underlie slow and progressive neurodegeneration. Mitochondrial calcium uniporter (MCU) is a crucial component that regulates the intramitochondrial Ca level. Ca uptake to the mitochondria by MCU, resulting in activation of mitochondrial dehydrogenases and stimulation of ATP synthesis, but excessive Ca uptake to the mitochondria resulting in cell apoptosis. Therefore, this study focused on whether MCU was involved in the apoptosis induced by 1-methyl-4-phenylpyridinium ions (MPP) in PC12 cells. Our results showed that the viability of PC12 cells was inhibited by MPP in a concentration-dependent and time-dependent manner. The expression of MCU was decreased gradually with a certain concentration of MPP. Meanwhile, MPP decreased the mitochondrial transmembrane potential and increased the apoptosis in PC12 cells. Notably, preincubated with Spermine, an MCU-specific agonist, or exogenously expressed MCU significantly alleviated cell apoptosis and decreased the reactive oxygen species production in PC12 cells that is induced by MPP treatment. Knockdown of endogenous MCU expression or preincubation with a specific inhibitor of MCU enhances the cell apoptosis and the reactive oxygen species in PC12. Thus, MCU is involved in the apoptosis in PC12 induced by MPP.