Apoptotic mechanisms in mutant LRRK2-mediated cell death

Iaccarino, Ciro; Crosio, Claudia; Vitale, Carmine; Sanna, Giovanna; Carrı̀, Maria Teresa; Barone, Paolo

doi:10.1093/hmg/ddm080

Cited by 175 publications

(162 citation statements)

References 40 publications

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“…When expressed in neuroblastoma cell line or cultured cortical neurons, mutant (G2019S) LRRK2 has been shown to induce apoptotic cell death by activating caspase-3 and caspase-8. [37][38][39] Our results provide the first in-vivo evidence that mutant (G2019S) LRRK2 causes the cell death of SN dopaminergic neurons by activating caspase-9 and caspase-8 through MKK4-JNK-c-Jun pathway.…”

Section: Discussionmentioning

confidence: 63%

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

Yh²,

et al. 2012

Cell Death Differ

155

151

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(G2019S) mutation of leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of both familial and sporadic Parkinson's disease (PD) cases. Twelve-to sixteen-month-old (G2019S) LRRK2 transgenic mice prepared by us displayed progressive degeneration of substantia nigra pars compacta (SNpc) dopaminergic neurons and parkinsonism phenotypes of motor dysfunction. LRRK2 is a member of mixed lineage kinase subfamily of mitogen-activated protein kinase kinase kinases (MAPKKKs). We hypothesized that (G2019S) mutation augmented LRRK2 kinase activity, leading to overphosphorylation of downstream MAPK kinase (MKK) and resulting in activation of neuronal death signal pathway. Consistent with our hypothesis, (G2019S) LRRK2 expressed in HEK 293 cells exhibited an augmented kinase activity of phosphorylating MAPK kinase 4 (MKK4) at Ser 257 , and protein expression of active phospho-MKK4 Ser257 was upregulated in the SN of (G2019S) LRRK2 transgenic mice. Protein level of active phospho-JNK Thr183/Tyr185 and phospho-c-Jun Ser63 , downstream targets of phospho-MKK4 Ser257 , was increased in the SN of (G2019S) LRRK2 mice. Upregulated mRNA expression of pro-apoptotic Bim and FasL, target genes of phospho-c-Jun Ser63 , and formation of active caspase-9, caspase-8 and caspase-3 were also observed in the SN of (G2019S) LRRK2 transgenic mice. Our results suggest that mutant (G2019S) LRRK2 activates MKK4-JNK-c-Jun pathway in the SN and causes the resulting degeneration of SNpc dopaminergic neurons in PD transgenic mice.

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Section: Discussionmentioning

confidence: 63%

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

Yh²,

et al. 2012

Cell Death Differ

155

151

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“…1) [31,66]. A 2-3-fold increase in kinase activity of G2019S LRRK2 compared with wild-type protein has been consistently seen by many groups [12,13,15,20,56,[67][68][69][70][71][72][73].…”

Section: Diversity Of Lrrk2 Mutationsmentioning

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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“…At least under the conditions of high-level expression of LRRK2 in vitro , mutant forms of LRRK2 are acutely toxic [23,27,29,47,50]. For G2019S LRRK2, there is evidence that cell death also occurs in vivo with viral vector-mediated expression [51,52].…”

Section: Pathogenic Mutations In Pd Affect Protein Functionmentioning

confidence: 99%

“…These domains may play a role in mediating the cytotoxicity induced by LRRK2 kinase activity. It has been shown that deletion of N-terminal LRR portion or WD40 of G2019S and/or R1441C rescued LRRK2-induced toxicity in neuronal cells [27,50]. This may be a point of therapeutic intervention by means of peptide inhibition in blocking the binding of proteins involved in mediating LRRK2-induced cytotoxicity as has been done for other globular proteins that interact [66].…”

Section: Therapeutic Strategies For Lrrk2-associated Parkinson's Diseasementioning

confidence: 99%

Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease?

Rudenko

Chia

Cookson

2012

BMC Med

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial Parkinson's disease (PD). Variation around the LRRK2 locus also contributes to the risk of sporadic PD. The LRRK2 protein contains a central catalytic region, and pathogenic mutations cluster in the Ras of complex protein C terminus of Ras of complex protein (mutations N1437H, R1441G/C and Y1699C) and kinase (G2019S and I2020T) domains. Much attention has been focused on the kinase domain, because kinase-dead versions of mutant LRRK2 are less toxic than kinase-active versions of the same proteins. Furthermore, kinase inhibitors may be able to mimic this effect in mouse models, although the currently tested inhibitors are not completely specific. In this review, we discuss the recent progress in the development of specific LRRK2 kinase inhibitors. We also discuss non-kinase-based therapeutic strategies for LRRK2-associated PD as it is possible that different approaches may be needed for different mutations.

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Apoptotic mechanisms in mutant LRRK2-mediated cell death

Cited by 175 publications

References 40 publications

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

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

Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease?

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