Phosphorylation of p53 by LRRK2 induces microglial tumor necrosis factor α-mediated neurotoxicity

Ho, Dong Hwan; Seol, Wongi; Eun, Jin Hwan; Son, Ilhong

doi:10.1016/j.bbrc.2016.11.163

Cited by 19 publications

(13 citation statements)

References 42 publications

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“…We have previously reported that LRRK2 phosphorylates p53 at T304 and T377 residues and the expression of phosphomimic p53 in BV2 cells induces TNFα expression and its release, resulting in neuronal death [ 19 ]. The combined evidence derived from our study suggests that G2019S LRRK2 contributed to the progression of PD by altering the physical condition of mitochondria in microglia during the neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies reported that inhibition of LRRK2 kinase activity or decreased expression of LRRK2 in microglia attenuated the pro-inflammatory response [ 15 16 17 ] whereas increased kinase activity of G2019S promotes inflammation [ 18 ]. Our previous study also suggested that p53 phosphorylation by LRRK2 contributed to tumor necrosis factor-α (TNFα) release in microglia, resulting in decreased neuronal survival [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

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LRRK2 Kinase Activity Induces Mitochondrial Fission in Microglia via Drp1 and Modulates Neuroinflammation

Lee

et al. 2018

Exp Neurobiol

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Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease (PD). LRRK2 contains a functional kinase domain and G2019S, the most prevalent LRRK2 pathogenic mutation, increases its kinase activity. LRRK2 regulates mitochondria morphology and autophagy in neurons. LPS treatment increases LRRK2 protein level and mitochondrial fission in microglia, and down-regulation of LRRK2 expression or inhibition of its kinase activity attenuates microglia activation. Here, we evaluated the direct role of LRRK2 G2019S in mitochondrial dynamics in microglia. Initial observation of microglia in G2019S transgenic mice revealed a decrease in mitochondrial area and shortage of microglial processes compared with their littermates. Next, we elucidated the molecular mechanisms of these phenotypes. Treatment of BV2 cells and primary microglia with LPS enhanced mitochondrial fission and increased Drp1, a mitochondrial fission marker, as previously reported. Importantly, both phenotypes were rescued by treatment with GSK2578215A, a LRRK2 kinase inhibitor. Finally, the protein levels of CD68, an active microglia marker, Drp1 and TNF-α were significantly higher in brain lysates of G2019S transgenic mice compared with the levels in their littermates. Taken together, our data suggest that LRRK2 could promote microglial mitochondrial alteration via Drp1 in a kinase-dependent manner, resulting in stimulation of pro-inflammatory responses. This mechanism in microglia might be a potential target to develop PD therapy since neuroinflammation by active microglia is a major symptom of PD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

LRRK2 Kinase Activity Induces Mitochondrial Fission in Microglia via Drp1 and Modulates Neuroinflammation

Lee

et al. 2018

Exp Neurobiol

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“…After inflammation induced by lipopolysaccharide, a robust induction of LRRK2 protein expression was observed in microglial cells ( Gillardon et al, 2012 ; Moehle et al, 2012 ). LRRK2 phosphorylated p53 in microglia and then increased the secretion of the pro-inflammatory cytokine TNFα ( Ho et al, 2017 ). In addition, knockdown of LRRK2 expression or pharmacological inhibition in microglia has been shown to alleviate pro-inflammatory signaling, including reduced levels of iNOS induction, p-p38, and transcriptional activity of NF-κB ( Kim et al, 2012 ; Moehle et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

LRRK2 Contributes to Secondary Brain Injury Through a p38/Drosha Signaling Pathway After Traumatic Brain Injury in Rats

Qin

Gao

et al. 2018

Front. Cell. Neurosci.

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Leucine-rich repeat kinase 2 (LRRK2) is widely expressed in the brain and exerts neurotoxicity in Parkinson’s disease. The p38/Drosha signaling activation has been reported to increase cell death under stress. This study was designed to investigate the potential role and mechanism of LRRK2 in secondary brain injury after traumatic brain injury (TBI). A total of 130 male Sprague-Dawley rats were examined using a weight-drop model of TBI. The rats received the specific LRRK2 inhibitor PF-06447475 or LRRK2 pDNA alone or in combination with Drosha pDNA. Real-time PCR, western blot, immunofluorescence, neuronal apoptosis, brain water content, and neurological score analyses were conducted. Our results showed that after TBI, endogenous LRRK2 expression and p38 phosphorylation were increased, whereas Drosha expression was inhibited. Administration of the LRRK2 inhibitor PF-06447475 significantly reduced neuronal apoptosis, brain water content, and blood–brain barrier permeability 12 h after TBI and ameliorated neurological deficits 72 h after TBI, which was concomitant with decreased p38 phosphorylation and increased Drosha expression. Conversely, LRRK2 overexpression induced the opposite effect. Moreover, the neurotoxic effects of LRRK2 on TBI were also eliminated by Drosha overexpression. Altogether, these findings demonstrate the importance of TBI-induced LRRK2 upregulation during the induction of post-traumatic neurological injury, which may be partially mediated through a p38/Drosha signaling pathway.

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“…Moreover, increased numbers of senescent astrocytes were observed in autopsied SNpc of PD patients relative to age-matched controls, and elevated levels of p16 INK4 protein and γH2AX foci, a marker of DNA damage, were also detected in the SNpc of PD patients [23,24]. Our previous study showed that the expression of TD-p53, a phosphomimetic form of LRRK2-mediated p53, increased the expression and release of the pro-inflammatory cytokine tumor necrosis factor α (TNFα), which is one of the SASP factors, in a BV2 murine microglial cell line [25]. However, we did not test p21, p16 INK4 , and βgal induction at that time.…”

Section: Accumulated Endogenous and Transmitted αSyn By Expression Ofmentioning

confidence: 97%

Upregulation of the p53-p21 pathway by G2019S LRRK2 contributes to the cellular senescence and accumulation of α-synuclein

Seol

Son

2019

Cell Cycle

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Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (LB) in neurons. α-Synuclein (αSyn) is a major component of LB and promote the PD pathogenesis via its accumulation by the impaired proteasomal or autophagic clearance. Numerous studies have revealed that the reduction of proteasome activity and autophagy is accelerated by cellular senescence. Leucine-rich repeat kinase 2 (LRRK2) contributes to PD progression and its most prevalent mutation, G2019S LRRK2, increases its activity. Our previous report has shown that the G2019S LRRK2 mutant promoted p53-induced p21 expression and neuronal cytotoxicity. The p53-p21 pathway plays a role in cellular senescence. We hypothesized that the loss of dopaminergic neurons by the stimulated p53-p21 pathway via the G2019S LRRK2 mutation might be associated with cellular senescence, thereby promoting the accumulation of αSyn. We confirmed that the ectopic expression of the phosphomimetic p53 mutant, p21, or G2019 in differentiated SH-SY5Y cells increased the following: 1) the expression of β-galactosidase, a marker of cellular senescence, and the activity of senescence-associated β-galactosidase, 2) endogenous αSyn protein level, but not its mRNA level, and 3) αSyn fibril accumulation in dSH-SY5Y via low proteasome and cathepsin D activities. Elevated oligomeric αSyn and the increase in β-galactosidase with induced p21 were observed in brain lysates of G2019S transgenic mice. Our results suggest that cellular senescence is promoted via the p53-p21 pathway due to the G2019S LRRK2 mutation. Eventually, decreased protein degradation by G2019S-mediated senescence could accelerate αSyn aggregate formation.

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Phosphorylation of p53 by LRRK2 induces microglial tumor necrosis factor α-mediated neurotoxicity

Cited by 19 publications

References 42 publications

LRRK2 Kinase Activity Induces Mitochondrial Fission in Microglia via Drp1 and Modulates Neuroinflammation

LRRK2 Kinase Activity Induces Mitochondrial Fission in Microglia via Drp1 and Modulates Neuroinflammation

LRRK2 Contributes to Secondary Brain Injury Through a p38/Drosha Signaling Pathway After Traumatic Brain Injury in Rats

Upregulation of the p53-p21 pathway by G2019S LRRK2 contributes to the cellular senescence and accumulation of α-synuclein

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