Chronic Manganese Exposure and the Enteric Nervous System: An
            <i>in Vitro</i>
            and Mouse
            <i>in Vivo</i>
            Study

Ghaisas, Shivani; Harischandra, Dilshan S.; Palanisamy, Bharathi N.; Proctor, Alexandra; Jin, Huajun; Dutta, Somak; Sarkar, Satyapriya; Langley, Monica R.; Zenitsky, Gary; Anantharam, Vellareddy; Kanthasamy, Arthi; Phillips, Gregory J

doi:10.1289/ehp7877

Cited by 16 publications

(3 citation statements)

References 79 publications

(130 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, studies in rodent models have demonstrated that αSyn originating from the gut (converted in situ from αSyn fibrils injected in) can spread to the brain through the vagus nerve in a prion-like manner, leading to features of PD (24). Mn is known to cause autonomic dysfunctions similar to PD (11), and the recent studies by Payami and coworkers have associated PD with widespread microbiome dysbiosis (25, 26). In this light, to better understand Mn toxicity and its links to PD, we took a non-targeted, multi-compartmental approach to probe metabolome-wide changes in vivo at an early timepoint of Mn exposure before the motor symptom sets in.…”

Section: Discussionmentioning

confidence: 99%

“…1E). Previous studies by our group and others have shown that Mn induced lysosomal and mitochondrial dysfunction in cell culture and rodent models (6,7,11,12). To validate if the cellular mechanisms of Mn toxicity are consistent in our fly model, we performed the LysoTracker assay on live fly brains.…”

Section: An Adult Drosophila Model Of Manganese Toxicity Recapitulate...mentioning

confidence: 94%

See 1 more Smart Citation

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

Lai,

Reina-Gonzalez,

Maor

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: An Adult Drosophila Model Of Manganese Toxicity Recapitulate...mentioning

confidence: 94%

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

Lai,

Reina-Gonzalez,

Maor

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Eight-week-old C57BL/6NCrl mice purchased from Charles River were orally gavaged with Mn (30 mg/kg) dissolved in ultrapure water daily for 30 days. This dose was chosen based on previous studies on mouse models of Mn neurotoxicity, which generally use the Mn doses between 5-30 mg/kg/day for periods of 21-120 days 83 . The control animals received daily injections of the same volume of water.…”

Section: Animal Studiesmentioning

confidence: 99%

Epitranscriptomic Reader YTHDF2 Regulates SEK1(MAP2K4)-JNK-cJUN Inflammatory Signaling in Astrocytes during Neurotoxic Stress

Malovic,

Ealy,

Hsu

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

As the most abundant glial cells in the CNS, astrocytes dynamically respond to neurotoxic stress, however, the key molecular regulators controlling the inflammatory status of these sentinels during neurotoxic stress have remained elusive. Herein, we demonstrate that the m6A epitranscriptomic mRNA modification tightly regulates the pro-inflammatory functions of astrocytes. Specifically, the astrocytic neurotoxic stresser, manganese (Mn), downregulated the m6A reader YTHDF2 in human and mouse astrocyte cultures and in the mouse brain. Functionally, YTHDF2 knockdown augmented, while its overexpression dampened, neurotoxic stress induced proinflammatory response, suggesting YTHDF2 serves as a key upstream regulator of inflammatory responses in astrocytes. Mechnistically, YTHDF2 RIP-sequencing identified MAP2K4 (MKK4; SEK1) mRNA as a YTHDF2 target influencing inflammatory signaling. Our target validation revealed Mn-exposed astrocytes mediates proinflammatory response by activating the phosphorylation of SEK1, JNK, and cJUN signaling. Collectively, YTHDF2 serves a key upstream molecular switch controlling SEK1(MAP2K4)-JNK-cJUN proinflammatory signaling in astrocytes.

show abstract

Trace metal elements: a bridge between host and intestinal microorganisms

Fei

Ding

et al. 2023

Sci. China Life Sci.

View full text Add to dashboard Cite

Chronic Manganese Exposure and the Enteric Nervous System: An in Vitro and Mouse in Vivo Study

Cited by 16 publications

References 79 publications

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

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

Epitranscriptomic Reader YTHDF2 Regulates SEK1(MAP2K4)-JNK-cJUN Inflammatory Signaling in Astrocytes during Neurotoxic Stress

Trace metal elements: a bridge between host and intestinal microorganisms

Contact Info

Product

Resources

About