The role of microglial LRRK2 kinase in manganese-induced inflammatory neurotoxicity via NLRP3 inflammasome and RAB10-mediated autophagy dysfunction

Pajarillo, Edward Alain B.; Kim, Sang Hoon; Digman, Alexis; Dutton, Matthew; Son, Deok‐Soo; Aschner, Michael; Lee, Eun-Sook

doi:10.1016/j.jbc.2023.104879

Cited by 14 publications

(5 citation statements)

References 73 publications

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“…Further, Mn can also intensify αSyn-induced inflammation, another hallmark of PD (7,17). Mn has also been recently shown to induce the expression of leucine-rich repeat kinase 2 (LRRK2), another key PARK gene that has been linked to PD etiology (18,19). For disease modeling, previous fly models of Mn toxicity were largely based on the developmental larvae, lacking relevance for occupational exposures to Mn occurring in adults, from whom the Mn-PD links were first drawn (10).…”

Section: Discussionmentioning

confidence: 99%

Biotin rescues manganese-induced Parkinson’s disease phenotypes and neurotoxicity

Lai,

Reina-Gonzalez,

Maor

et al. 2023

Preprint

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Occupational exposure to manganese (Mn) induces manganism and has been widely linked as a contributing environmental factor to Parkinson’s disease (PD), featuring dramatic signature overlaps between the two in motor symptoms and clinical hallmarks. However, the molecular mechanism underlying such link remains elusive, and for combating PD, effective mechanism-based therapies are lacking. Here, we developed an adultDrosophilamodel of Mn toxicity to recapitulate key parkinsonian features, spanning behavioral deficits, neuronal loss, and dysfunctions in lysosome and mitochondria. We performed global metabolomics on flies at an early stage of toxicity and identified metabolism of the B vitamin, biotin (vitamin B7), as a master pathway underpinning Mn toxicity with systemic, body–brain increases in Mn-treated groups compared to the controls. Using BtndRNAimutant flies, we show that biotin depletion exacerbates Mn-induced neurotoxicity, parkinsonism, and mitochondrial dysfunction; while in Mn-exposed wild-type flies, biotin feeding dramatically ameliorates these pathophenotypes. We further show in human induced stem cells (iPSCs)- differentiated midbrain dopaminergic neurons that the supplemented biotin protects against Mn-induced neuronal loss, cytotoxicity, and mitochondrial dysregulation. Finally, human data profiling biotin-related proteins show for PD cases elevated circulating levels of biotin transporters but not of metabolic enzymes compared to healthy controls, suggesting humoral biotin transport as a key event involved in PD. Taken together, our findings identified compensatory biotin pathway as a convergent, systemic driver of Mn toxicity and parkinsonian pathology, providing new basis for devising effective countermeasures against manganism and PD.Significance StatementEnvironmental exposure to manganese (Mn) may increase the risk for Parkinson’s disease (PD); however, the mechanistic basis linking the two remains unclear. Our adult fruit fly (Drosophila) model of Mn toxicity recapitulated key Parkinson’s hallmarksin vivospanning behavioral deficits, neuronal loss, and mitochondrial dysfunction. Metabolomics identified the biotin (vitamin B7) pathway as a key mediator, featuring systemic biotin increases in the flies. Rescue trials leveraging biotin-deficient flies, wild-type flies, and human iPSC-derived dopaminergic neurons determined biotin as a driver of manganism, with the parkinsonian phenotypes dramatically reversed through biotin supplementation. Our findings, in line with overexpressed circulating biotin transporters observed in PD patients, suggest compensatory biotin pathway as a key to untangle the Mn-PD link for combating neurodegenerative disease.

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Section: Discussionmentioning

confidence: 99%

Biotin rescues manganese-induced Parkinson’s disease phenotypes and neurotoxicity

Lai,

Reina-Gonzalez,

Maor

et al. 2023

Preprint

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“…After six hours of exposure, Mn increased protein levels of autophagy-related markers (LC3-II, ATG5, BECN1, SQSTM1, and CTSB), concomitant with double-membrane autophagosomes, dysfunctional lysosomes, and mitochondrial vacuoles observed under electronic microscopy [116]. Moreover, Mn induced toxicity in microglial BV2 cells via the LRRK2-RAB10-CTSB-NLRP3 pathway-mediated autophagy dysfunction and inflammasome [120].…”

Section: Autophagymentioning

confidence: 95%

“…In this alternative mechanism, Mn (100 µM, 24 h) produces mitochondrial dysfunction in primary microglial cells primed with LPS for 3 h, decreasing the expression of the mitochondrial fusion protein 2 (mitofusin 2) and vacuolar protein sorting associate protein 35 (VPS35), a retromer complex protein that induces mitofusin 2 ubiquitination [111]. A recent study demonstrated a new mechanism that mediates NLRP3 inflammasome activation, where LRRK2 (leucine-rich repeat kinase 2) triggers Mn-induced NLRP3-CASP1 inflammasome activation in BV2 cells (250 µM for 6, 12, or 24 h) and male C57BL/6 mice (30 mg/kg Mn, 3 weeks) [120]. Moreover, the Mn-induced NLRP3-CASP1 inflammasome pathway in mouse neuroblastoma (N2a) cells (250, 500, and 1000 µM Mn for 24 h and 48 h) and Mn-exposed male SD rats (25 mg/kg Mn, 30 days) mediates KH-type splicing regulatory protein (KHSRP) expression [121].…”

Section: Nlrp3-casp1 Signaling Pathwaymentioning

confidence: 99%

Signaling Pathways Involved in Manganese-Induced Neurotoxicity

Cheng,

Villahoz,

Ponzio

et al. 2023

Cells

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Manganese (Mn) is an essential trace element, but insufficient or excessive bodily amounts can induce neurotoxicity. Mn can directly increase neuronal insulin and activate insulin-like growth factor (IGF) receptors. As an important cofactor, Mn regulates signaling pathways involved in various enzymes. The IGF signaling pathway plays a protective role in the neurotoxicity of Mn, reducing apoptosis in neurons and motor deficits by regulating its downstream protein kinase B (Akt), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR). In recent years, some new mechanisms related to neuroinflammation have been shown to also play an important role in Mn-induced neurotoxicity. For example, DNA-sensing receptor cyclic GMP–AMP synthase (cCAS) and its downstream signal efficient interferon gene stimulator (STING), NOD-like receptor family pyrin domain containing 3(NLRP3)-pro-caspase1, cleaves to the active form capase1 (CASP1), nuclear factor κB (NF-κB), sirtuin (SIRT), and Janus kinase (JAK) and signal transducers and activators of the transcription (STAT) signaling pathway. Moreover, autophagy, as an important downstream protein degradation pathway, determines the fate of neurons and is regulated by these upstream signals. Interestingly, the role of autophagy in Mn-induced neurotoxicity is bidirectional. This review summarizes the molecular signaling pathways of Mn-induced neurotoxicity, providing insight for further understanding of the mechanisms of Mn.

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“…In vivo, it has been shown that cholinergic neurons in the striatum of LRRK2 R1441C knock-in mice develop ciliation defects, likely due to Rab10 over-phosphorylation [79], and a similar ciliation phenotype was subsequently observed also in astrocytes of LRRK2 G2019S knock-in mice [166]. Regarding the effects of Rab phosphorylation in microglia, it has been shown that microglial LRRK2 and Rab10 mediate manganese-induced inflammation and neurotoxicity [167]. In addition, since much of the work on LRRK2 and Rab has been conducted using macrophage cells like RAW264.7 cells, these findings would also apply to microglia, which are macrophage-lineage cells.…”

Section: Rab Phosphorylation In Relation To Pdmentioning

confidence: 99%

An Update on the Interplay between LRRK2, Rab GTPases and Parkinson’s Disease

Komori,

Kuwahara

2023

Biomolecules

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Over the last decades, research on the pathobiology of neurodegenerative diseases has greatly evolved, revealing potential targets and mechanisms linked to their pathogenesis. Parkinson’s disease (PD) is no exception, and recent studies point to the involvement of endolysosomal defects in PD. The endolysosomal system, which tightly controls a flow of endocytosed vesicles targeted either for degradation or recycling, is regulated by a number of Rab GTPases. Their associations with leucine-rich repeat kinase 2 (LRRK2), a major causative and risk protein of PD, has also been one of the hot topics in the field. Understanding their interactions and functions is critical for unraveling their contribution to PD pathogenesis. In this review, we summarize recent studies on LRRK2 and Rab GTPases and attempt to provide more insight into the interaction of LRRK2 with each Rab and its relationship to PD.

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The role of microglial LRRK2 kinase in manganese-induced inflammatory neurotoxicity via NLRP3 inflammasome and RAB10-mediated autophagy dysfunction

Cited by 14 publications

References 73 publications

Biotin rescues manganese-induced Parkinson’s disease phenotypes and neurotoxicity

Biotin rescues manganese-induced Parkinson’s disease phenotypes and neurotoxicity

Signaling Pathways Involved in Manganese-Induced Neurotoxicity

An Update on the Interplay between LRRK2, Rab GTPases and Parkinson’s Disease

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