LRRK2 Modulates Vulnerability to Mitochondrial Dysfunction in Caenorhabditis elegans

Saha, Sudipta; Guillily, Maria D.; Ferree, Andrew; Lanceta, Joel; Chan, D.; Ghosh, Jayita; Hsu, Cindy H.; Segal, Lilach; Raghavan, Kesav; Matsumoto, Kunihiro; Hisamoto, Naoki; Kuwahara, Tomohiro; Iwatsubo, Takeshi; Moore, Landon L.; Goldstein, Lee E.; Cookson, Mark; Wolozin, Benjamin

doi:10.1523/jneurosci.2281-09.2009

Cited by 221 publications

(246 citation statements)

References 54 publications

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“…Transgenic overexpression of human I2020T LRRK2 in Drosophila also induces DA neuron degeneration by a mechanism that is proposed to involve phosphorylation of 4E-BP [75], although this mechanism is controversial [72,119]. Overexpression of human LRRK2 in Caenorhabditis elegans also mediate age-dependent DA neurodegeneration, reduction of dopamine levels in vivo, behavioral deficits, and locomotor dysfunction that is more profound for G2019S than wild-type protein [120,121]. Transgenic expression of human R1441C mutant LRRK2 in C. elegans induces age-dependent DA neurodegeneration and locomotor deficit accompanied by a reduction in dopamine levels [120].…”

Section: Direct Toxic Effects Of Lrrk2 Expression In Neuronsmentioning

confidence: 99%

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

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Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

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Section: Direct Toxic Effects Of Lrrk2 Expression In Neuronsmentioning

confidence: 99%

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

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“…Another gain in case P72 included the entire LRRK2 gene; point mutations but not gains in this gene are found in patients with Parkinson's disease. Of note, it has been described that overexpression of wild-type human LRRK2 protects Caenorhabditis elegans after exposure to mitochondrial toxins, 17 and therefore this gain of the intact gene may have contributed to the development of MDS.…”

Section: Individual Additional Aberrationsmentioning

confidence: 99%

Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance

et al. 2011

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About 40% of patients with myelodysplastic syndromes (MDSs) present with a normal karyotype, and they are facing different courses of disease. To advance the biological understanding and to find molecular prognostic markers, we performed a highresolution oligonucleotide array study of 107 MDS patients (French American British) with a normal karyotype and clinical follow-up through the Duesseldorf MDS registry. Recurrent hidden deletions overlapping with known cytogenetic aberrations or sites of known tumor-associated genes were identified in 4q24 (TET2, 2x), 5q31.2 (2x), 7q22.1 (3x) and 21q22.12 (RUNX1, 2x). One patient with a 7q22.1 deletion had an additional 5q31.2 deletion of the acute myeloid leukemia/MDS region, the smallest deletion identified so far and including the putative tumor suppressor (ts) genes, EGR1 and CTNNA1. One TET2 deletion was homozygous and one heterozygous, with a missense mutation in the remaining allele, further supporting its role as a ts gene. Besides these recurrent alterations, additional individual imbalances were found in 34 cases; in total, 42/107 (39%) cases had genomic imbalances. These patients had an inferior survival as compared with the rest of the patients (P ¼ 0.002). This study emphasizes the heterogeneity of MDS, but points to interesting genes that may have diagnostic and prognostic impact.

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“…Paraquat is widely used for ROS induction as a pharmacological reagent (26)(27)(28)(29). Synchronized L1 wildtype worms were cultured on nematode growth medium (NGM) plates containing 0.3 mM paraquat for three days.…”

Section: Glb-13 Is Upregulated By Paraquat Exposurementioning

confidence: 99%

GLB‐13 is associated with oxidative stress resistance in caenorhabditis elegans

Ren

Han

et al. 2013

IUBMB Life

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Globins constitute a superfamily of heme-binding proteins that is widely present in many species. There are 33 putative globins in the genome of Caenorhabditis elegans, where glb-13 is a homolog of neuroglobin (Ngb) based on sequence analysis and specific expression in neurons. Here we examined whether glb-13 as well as Ngb is also associated with resistance to reactive oxygen species (ROS) induced by paraquat. Our results showed that the mRNA level of glb-13 was significantly upregulated after paraquat exposure. Expression of a green fluorescent protein (GFP) reporter gene directed by the glb-13 promoter was increased by paraquat exposure. The mutant C. elegans strain glb-13(tm2825) was sensitive to paraquat-induced oxidative stress. Overexpression of human Ngb (hNgb) in C. elegans neuronal cells can rescue the paraquat sensitive phenotype of the mutant strain. glb-13 mutation or hNgb overexpression did not affect the expression of antioxidant enzymes such as superoxide dismutase (SOD). To examine the ROS-scavenging capabilities of hNgb and glb-13, we further examined the level of ROS in glb-13 mutant and hNgb transgenic (hNgb-Tg) worms. There was no statistical difference in ROS levels in the untreated controls; however in paraquattreated worms, the ROS level was statistically repressed in the hNgb-Tg relative to enhanced green fluorescent protein (EGFP)-Tg worms or wildtype animals. Additionally, the ROS level of glb-13 mutant was statistically higher than the wildtype animals. Furthermore, hNgb overexpression diminished the ROS level of glb-13 mutant. In conclusion, hNgb can rescue the ROS sensitive phenotype of the glb-13 mutant strain. The protein GLB-13 seems to have an hNgb-like function, suggesting the importance of the globin protein family in maintaining the homeostasis of ROS signals. Our data provided evidence for the first time that glb-13 is associated with the resistance against oxidative stress-induced toxicity.

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LRRK2 Modulates Vulnerability to Mitochondrial Dysfunction in Caenorhabditis elegans

Cited by 221 publications

References 54 publications

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance

GLB‐13 is associated with oxidative stress resistance in caenorhabditis elegans

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