Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease

Tezuka, Toshiki; Taniguchi, Daisuke; Sano, Mariko; Shimada, Tomoyo; Oji, Yusuke; Tsunemi, Taiji; Ikeda, Aya; Li, Yuanzhe; Yoshino, Hideaki; Ogata, Jun; Shiba‐Fukushima, Kahori; Funayama, Manabu; Nishioka, Kenya; Imai, Yuzuru

doi:10.1038/s41531-022-00367-y

Cited by 12 publications

(4 citation statements)

References 59 publications

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“…Mutant LRRK2-mediated Rab phosphorylation can cause endocytic defects (Liu et al, 2020; Rivero-Ríos et al, 2020; Streubel-Gallasch et al, 2021), and LRRK2-modified Rab10 localizes to and promotes secretion from stressed lysosomes (Eguchi et al, 2018; Kluss et al, 2022). Interestingly, phosphorylated Rab10 (pRab10) levels are elevated in the CNS of AD and PD patients, and pRab10 has been reported to co-localize with pathological tau (Yan et al, 2018; Tezuka et al, 2022) suggesting that post-translational modification of Rab10 modifies the disease state. Whether Rab10’s phosphorylation status affects its ability to regulate prion-like activity of mHTT ex1 or other amyloid aggregates warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Impairment of the glial phagolysosomal system drives prion-like propagation in aDrosophilamodel of Huntington’s disease

Davis,

Zaya,

Panning Pearce

2023

Preprint

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Amyloid aggregate accumulation and spread between synaptically-connected regions of the brain is a hallmark of neurodegenerative disease progression. Glia participate in neuropathogenesis by reducing protein aggregate loads via phagocytosis while simultaneously acting as vectors for aggregate spread between cells. Emerging evidence supports the hypothesis that aggregate accumulation compromises the ability of glia to clear toxic material from the brain, possibly by disrupting the phagolysosomal compartment. A better understanding of how glia become deficient in the disease state could reveal novel therapeutic targets. Here, we report that mutant huntingtin (mHTT) aggregates impair glial responsiveness to injury and capacity to degrade axonal debris in aDrosophilamodel of Huntington’s disease (HD). mHTT aggregate formation in neurons slowed engulfment and clearance of injured axons and caused accumulation of late phagosomes and lysosomes in glia. Neuronal mHTT expression induced innate immunity and phagocytic genes, some of which regulated mHTT aggregate burden in the brain. A forward genetic screen targeting glial Rab GTPases revealed Rab10 as a novel modifier of mHTT aggregate transmission from neurons to glia that acts downstream of the phagocytic receptor, Draper. This suggests that Rab-mediated intercellular vesicle sorting mechanisms could create opportunities for prion-like mHTT aggregates to escape lysosomal degradation. Together, our findings support a model in which mHTT aggregate build-up within the phagolysosomal system impairs glial phagocytosis while also promoting the generation of seeding-competent pathological proteins. The new mechanistic information we report here adds to a growing recognition of phagocytic glia as double-edged players in prion-like proteopathies such as HD.SIGNIFICANCE STATEMENTDeposition of amyloid aggregates is closely associated with neurodegenerative disease progression and neuronal death. Recent studies highlight glia as dynamic mediators of disease, capable of phagocytosing dying neurons and amyloid aggregates, while also inducing chronic inflammation and promoting proteopathic spread. Thus, glia have emerged as promising therapeutic targets for disease intervention. Here, we demonstrate in aDrosophilamodel of Huntington’s disease that neuronal mHTT aggregates interfere with glial phagocytic functions, stimulate innate immunity signaling, and impair phagolysosomal processing. We also identify Rab10 as a novel modifier of prion-like transmission of mHTT aggregates, suggesting that Rab-mediated intramembrane fusion in the phagolysosomal system could drive aggregate pathology spread.

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Section: Discussionmentioning

confidence: 99%

Impairment of the glial phagolysosomal system drives prion-like propagation in aDrosophilamodel of Huntington’s disease

Davis,

Zaya,

Panning Pearce

2023

Preprint

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“…Notably, this variant has been identified in approximately 5% of the population, a classification that aligns with ACMG’s BS1 (Strong benign criteria), and has also received a benign classification from in silico prediction tools (BP4). Nevertheless, the biochemical assessment of LRRK2 G2385R in postmortem brain samples from Parkinson’s disease patients has revealed heightened kinase activity and synucleinopathy as distinctive pathological features (19). Despite its classification as benign according to ACMG guidelines, the presence of this mutation in a significant number of sporadic PD cases suggests a narrative that diverges from its classification.…”

Section: Discussionmentioning

confidence: 99%

DystoGen Compendium: A comprehensive resource of ACMG annotated movement disorder associated genetic variants

Saikia,

Gaharwar,

Poojary

et al. 2023

Preprint

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PurposeIn recent years, the advent of high throughput sequencing techniques has led to the identification of a number of genetic variants across different genes that are associated with movement disorders. However, the under-appreciation of the variant spectrum in movement disorders and the lack of consolidated and systematic evidence-based annotation of these variants has long undermined the true potential of genomic approaches to expedite precision medicine.MethodsWe manually curated the genetic variants from a panel of 118 genes that have been associated with monogenic causes of movement disorders and systematically annotated them according to ACMG & AMP (American College of Medical Genetics and the Association of Molecular Pathologists) guidelines.ResultsData integration after systematic classification of variants according to ACMG & AMP guidelines showed 5118 pathogenic/likely pathogenic variants accounting for 18.03% of the total unique variants being annotated. This data and annotations are available in a comprehensive online compendium DystoGen.ConclusionTo the best of our knowledge, this is the most comprehensive compendium of genetic variants in movement disorders annotated as per the ACMG & AMP guidelines for pathogenicity. The compendium indexes 28377 variants along with a wide array of information including the geographical origin of the variant, global distribution, and population allele frequency. The resource has been made available in the URLhttps://clingen.igib.res.in/dystogen/.

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“…LRRK2 mutation is the most common etiology of familial PD. Notably, the G2385R variant is a common PD risk allele in Asian populations, and individuals, harboring this mutation exhibit elevated levels of LRRK2 kinase and pro‐inflammatory factors in the brain, in addition to displaying levodopa‐responsive Parkinson's syndrome at an early stage, Lewy body formation, neurofibrillary tangles, and mild neuroinflammation on histopathological examination (Tezuka et al, 2022). Similarly, It is reported that the G2019S mutation can increase LRRK2 kinase activity and aggravate neuronal death, while carriers of the G2019S mutation show elevated levels of peripheral pro‐inflammatory cytokines (Gardet et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

LRRK2 regulates ferroptosis through the system Xc‐GSH–GPX4 pathway in the neuroinflammatory mechanism of Parkinson's disease

Zheng,

Zhang,

Liu

et al. 2024

Journal Cellular Physiology

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Parkinson's disease (PD) is the most prevalent neurodegenerative disorder. Neuroinflammation mediated by activated microglia and apoptosis of dopaminergic (DA) neurons in the midbrain are its primary pathological manifestations. Leucine‐rich repeat protein kinase 2 (LRRK2) kinase has been observed to increase expression during neuroinflammation, however, the effect of LRRK2 on microglia activation remains poorly understood. In this study, we have established lipopolysaccharide (LPS) treated BV2 cells and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) models for both in vivo and in vitro investigation. Our data in vivo reveal that LRRK2 can promote microglia activation by regulating ferroptosis and activating nuclear factor‐κB. Inhibition of LRRK2 expression effectively suppressed the LPS‐induced pro‐inflammatory cytokines and facilitated the secretion of neuroprotective factors. Importantly, by co‐overexpressing LRRK2 and glutathione peroxidase 4 (GPX4), we identified the system Xc‐GSH–GPX4 pathway as a crucial component in LRRK2‐mediated microglial ferroptosis and inflammatory responses. Using a microglial culture supernatant (MCS) transfer model, we found that inhibiting LRRK2 or downregulating ferroptosis in BV2 cells prevented SH‐SY5Y cell apoptosis. Additionally, we observed abundant expression of LRRK2 and P‐P65 in the midbrain, which was elevated in the MPTP‐induced PD model, along with microglia activation. LRRK2 and P‐P65 expression inhibition with PF‐06447475 attenuated microglia activation in the nigrostriatal dense part of MPTP‐treated mice. Based on our findings, it is evident that LRRK2 plays a critical role in promoting the neuroinflammatory response during the pathogenesis of PD by regulating the system Xc‐GSH–GPX4 pathway. Taken together, our data highlights the potential research and therapeutic value of targeting LRRK2 to regulate neuroinflammatory response in PD through ferroptosis.

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Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease

Cited by 12 publications

References 59 publications

Impairment of the glial phagolysosomal system drives prion-like propagation in aDrosophilamodel of Huntington’s disease

Impairment of the glial phagolysosomal system drives prion-like propagation in aDrosophilamodel of Huntington’s disease

DystoGen Compendium: A comprehensive resource of ACMG annotated movement disorder associated genetic variants

LRRK2 regulates ferroptosis through the system Xc‐GSH–GPX4 pathway in the neuroinflammatory mechanism of Parkinson's disease

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