The role of posttranslational modifications of α-synuclein and LRRK2 in Parkinson's disease: Potential contributions of environmental factors

Pajarillo, Edward Alain B.; Rizor, Asha; Lee, Jayden; Aschner, Michael; Lee, Eun-Sook

doi:10.1016/j.bbadis.2018.11.017

Cited by 32 publications

(33 citation statements)

References 149 publications

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“…Growing evidence implicates both genetic and environmental factors in the development of neurodegenerative disorders such as PD and manganism [52]. This pathogenesis is likely mediated by the microglial inflammatory response, but whether or not environmental toxicants such as Mn are associated with LRRK2-induced pathological mechanisms is still unknown.…”

Section: Introductionmentioning

confidence: 99%

LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia

et al. 2019

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Long-term exposure to elevated levels of manganese (Mn) causes manganism, a neurodegenerative disorder with Parkinson’s disease (PD)-like symptoms. Increasing evidence suggests that leucine-rich repeat kinase 2 (LRRK2), which is highly expressed in microglia and macrophages, contributes to the inflammation and neurotoxicity seen in autosomal dominant and sporadic PD. As gene-environment interactions have emerged as important modulators of PD-associated toxicity, LRRK2 may also mediate Mn-induced inflammation and pathogenesis. In this study, we investigated the role of LRRK2 in Mn-induced toxicity using human microglial cells (HMC3), LRRK2-wild-type (WT) and LRRK2-knockout (KO) RAW264.7 macrophage cells. Results showed that Mn activated LRRK2 kinase by phosphorylation of its serine residue at the 1292 position (S1292) as a marker of its kinase activity in macrophage and microglia, while inhibition with GSK2578215A (GSK) and MLi-2 abolished Mn-induced LRRK2 activation. LRRK2 deletion and its pharmacological inhibition attenuated Mn-induced apoptosis in macrophages and microglia, along with concomitant decreases in the pro-apoptotic Bcl-2-associated X (Bax) protein. LRRK2 deletion also attenuated Mn-induced production of reactive oxygen species (ROS) and the pro-inflammatory cytokine TNF-α. Mn-induced phosphorylation of mitogen-activated protein kinase (MAPK) p38 and ERK signaling proteins was significantly attenuated in LRRK2 KO cells and GSK-treated cells. Moreover, inhibition of MAPK p38 and ERK as well as LRRK2 attenuated Mn-induced oxidative stress and cytotoxicity. These findings suggest that LRRK2 kinase activity plays a critical role in Mn-induced toxicity via downstream activation of MAPK signaling in macrophage and microglia. Collectively, these results suggest that LRRK2 could be a potential molecular target for developing therapeutics to treat Mn-related neurodegenerative disorders.

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Section: Introductionmentioning

confidence: 99%

LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia

et al. 2019

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“…Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the most prevalent movement disorder worldwide [1]. PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and often the presence of cytoplasmic protein aggregates known as Lewy bodies, which result in decreased neurotransmission and motor deficits [2].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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“…Both the systemic administration and regional injection of rotenone can reproduce the pathological hallmarks of PD as well as some Parkinsonian motor deficits, such as bradykinesia, rigidity, and a stooped-like posture [3,4]. In addition, studies with primary cultured dopaminergic neurons and SH-SY5Y cells have also shown the neurotoxicity of rotenone [5,6].…”

Section: Introductionmentioning

confidence: 99%

Involvement of Akt/mTOR in the Neurotoxicity of Rotenone-Induced Parkinson’s Disease Models

Zhang

Guo

et al. 2019

IJERPH

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Rotenone has recently been widely used to establish Parkinson’s disease (PD) models to replicate the features of PD. However, the mechanisms involved in rotenone neurotoxicity have not been elucidated. The aim of the present study was to identify the neurotoxicity of rotenone through intraperitoneal injection in mice and to investigate the global changes of phosphorylation proteomic profiles in rotenone-injured SH-SY5Y cells through a label-free proteomic analysis using a PTMScan with LC–MS/MS. ICR (Institute of Cancer Research) mice were intraperitoneally injected with different dosages of rotenone (1 mg/kg/d or 3 mg/kg/d) daily for 21 consecutive days. Rotenone caused a dose-dependent decrease in locomotor activities and a decrease in the number of Nissl-positive and tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra pars compacta (SNpc). Here, 194 phosphopeptides on 174 proteins were detected in SH-SY5Y cells, and 37 phosphosites on 33 proteins displayed statistically significant changes in expression after rotenone injury. The downregulation of phosphorylated Akt and mTOR was further confirmed by western blot analysis. A specific Akt activator, SC79, could protect cell viability and induce autophagy in rotenone-injured SH-SY5Y cells. This study indicates the involvement of the Akt/mTOR (mammalian target of rapamycin) signaling pathway in rotenone-injured SH-SY5Y cells and provides molecular information for the neurotoxicity of rotenone.

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The role of posttranslational modifications of α-synuclein and LRRK2 in Parkinson's disease: Potential contributions of environmental factors

Cited by 32 publications

References 149 publications

LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia

LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia

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

Involvement of Akt/mTOR in the Neurotoxicity of Rotenone-Induced Parkinson’s Disease Models

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