G2019S LRRK2 mutant fibroblasts from Parkinson’s disease patients show increased sensitivity to neurotoxin 1-methyl-4-phenylpyridinium dependent of autophagy

Yakhine-Diop, Sokhna M. S.; Pedro, José Manuel Bravo-San; Gómez-Sánchez, Rubén; Pizarro-Estrella, Elisa; Rodríguez-Arribas, Mario; Climent, Vicente; Aiastui, Ana; Munáin, Adolfo López de; Fuentes, José; González‐Polo, Rosa A.

doi:10.1016/j.tox.2014.07.001

Cited by 44 publications

(33 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mitochondrial dysfunction likely plays a role in the manifestation of the disease later in life. Recapitulating the impact of “mitochondrial aging” in vitro , using juvenile cells has been challenging; however, we and others have previously shown robust phenotypes of LRRK2, PINK1, and Parkin mutant PD patient fibroblasts when subjected to low doses of small molecules which induce specific mitochondrial stress [10, 11, 18, 20]. In order to determine the unique features of individuals with sporadic PD, we use fibroblast samples (Supp.…”

Section: Resultsmentioning

confidence: 99%

Fibroblast Biomarkers of Sporadic Parkinson’s Disease and LRRK2 Kinase Inhibition

et al. 2015

View full text Add to dashboard Cite

It has been uncertain whether specific disease-relevant biomarker phenotypes can be found using sporadic Parkinson’s disease (PD) patient-derived samples, as it has been proposed that there may be a plethora of underlying causes and pathological mechanisms. Fibroblasts derived from familial PD patients harboring leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1 (PINK1), and Parkin mutations show clear disease-relevant mitochondrial phenotypes, which are exacerbated under conditions of pharmacological stress. We utilized fibroblasts derived from non-familial sporadic PD patients (without LRRK2 mutations) or LRRK2 mutation carriers to directly compare the cellular phenotypes during and after mitochondrial stress. We then determined the effects of pharmacological LRRK2 kinase inhibition using LRRK2-in-1. We found that there were two distinct populations of sporadic PD patient-derived fibroblast lines. One group of sporadic PD lines was highly susceptible to valinomycin-induced mitochondrial depolarization, emulating the mutant LRRK2 phenotype. These lines showed elevated mitochondrial superoxide/ nitric oxide levels, displayed increased mitochondrial and lysosome co-localization, and an increased rate of mitochondrial collapse, which corresponded with changes in mitochondrial fission and fusion proteins. The application of LRRK2-in-1 reversed decreased levels of mitochondrial and lysosome co-localization and partially restored mitochondrial network associated proteins and the mitochondrial membrane potential in the fibroblasts. This study identifies novel mitochondrial biomarkers in sporadic PD patient-derived fibroblast lines, which could be used as preclinical tools in which to test novel and known neuroprotective compounds.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-015-9435-4) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultsmentioning

confidence: 99%

Fibroblast Biomarkers of Sporadic Parkinson’s Disease and LRRK2 Kinase Inhibition

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Since the dynamic nature of the autophagy pathway makes interpretation of LC3-II levels difficult, future studies to measure autophagic flux will require measurement of these responses following administration of autophagy inducers and inhibitors. There is certainly convincing evidence linking LRRK2 and autophagy/mitophagy (Ramonet et al, 2011; Tong et al, 2012; Cherra et al, 2013; Hindle et al, 2013; Orenstein et al, 2013; Schapansky et al, 2014) with regulating roles for LRRK2 involving mTor signaling (Ferree et al, 2012; Manzoni et al, 2013; Schapansky et al, 2014, Herzig, 2011 #75; Yakhine-Diop et al, 2014), calcium homeostasis (Cherra et al, 2013) and MEK signaling (Hindle et al, 2013). This involvement of LRRK2 in autophagic pathways goes along with the role of LRRK2 regulating synaptic via vesicle trafficking and neurotransmitter release.…”

Section: Discussionmentioning

confidence: 99%

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice

Yue

Hinkle

Davies

et al. 2015

Neurobiology of Disease

221

214

View full text Add to dashboard Cite

Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson’s disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock in mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24 months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6 months, by 12 months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug- evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S mice, which are consistent with mitochondrial fission arrest. We anticipate the G2019S will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression.

show abstract

“…The effects of G2019S on neurite length can be abolished by down-regulation of LC3 or Atg7 and enhanced by autophagy inducer rapamycin, hinting that autophagy plays an important role in regulation of neurite length [75]. In fibroblasts, G2019S LRRK2 mutant exacerbates MPTP-induced cell death dependent of autophagic activity [76]. Furthermore, a study showed that LRRK2 increases the number of autophagosomes by activating CaMKK/AMPK pathway [73].…”

Section: Pd-related Genes Are Involved In Dysregulation Of Autophagy mentioning

confidence: 99%

“…The loss of lysosomal glucocerebrosidase is directly related to reduced lysosomal CMA activity, increased α-synuclein and decreased ceramide, which suggests that compromise in lysosomal function contributes to PD pathology [93]. One study also shows that the fibroblasts from PD patients with the mutation G2019S have higher level of autophagy compared with wild type fibroblasts, which contributes to the more vulnerability to MPP + [76]. However, another study using the primary cultured fibroblasts from sporadic PD patients detects no changes in autophagy [94].…”

Section: Recent Findings On Autophagy From Pd Human Tissuesmentioning

confidence: 99%

Dysregulation of autophagy and mitochondrial function in Parkinson’s disease

Bao

Abraham

Gao

et al. 2016

Transl Neurodegener

View full text Add to dashboard Cite

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Increasing evidence supports that dysregulation of autophagy and mitochondrial function are closely related with PD pathogenesis. In this review, we briefly summarized autophagy pathway, which consists of macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). Then, we discussed the involvement of mitochondrial dysfunction in PD pathogenesis. We specifically reviewed the recent developments in the relationship among several PD related genes, autophagy and mitochondrial dysfunction, followed by the therapeutic implications of these pathways. In conclusion, we propose that autophagy activity and mitochondrial homeostasis are of high importance in the pathogenesis of PD. Better understanding of these pathways can shed light on the novel therapeutic methods for PD prevention and amelioration.

show abstract

G2019S LRRK2 mutant fibroblasts from Parkinson’s disease patients show increased sensitivity to neurotoxin 1-methyl-4-phenylpyridinium dependent of autophagy

Cited by 44 publications

References 42 publications

Fibroblast Biomarkers of Sporadic Parkinson’s Disease and LRRK2 Kinase Inhibition

Fibroblast Biomarkers of Sporadic Parkinson’s Disease and LRRK2 Kinase Inhibition

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice

Dysregulation of autophagy and mitochondrial function in Parkinson’s disease

Contact Info

Product

Resources

About