Our data suggest that the LRRK2G2019S mutation plays an important role in the causality of familial and sporadic Parkinson disease (PD) in Israel and that gender affects its frequency among patients.
The localization of LRRK2 to key neuronal populations throughout the nigrostriatal dopaminergic pathway is consistent with the involvement of LRRK2 in the molecular pathogenesis of familial and sporadic parkinsonism.
Subsequent studies have also insinuated mutations in leucine repeat kinase-2 (LRRK2), Parkin, PTEN-induced putative kinase 1 (PINK1), as well as DJ-1 causing familial forms of PD.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most prevalent genetic cause of both familial (PARK8 type with autosomal dominant inheritance) and sporadic PD.
We used a multiple logistic regression model with backward variable selection, validated with bootstrap resampling, to establish the best combination of motor and nonmotor features that differentiates nonparkinsonian first-degree relatives of LRRK2G2019Sfamilial PD cases from unrelated healthy controls.
Mutations in Leucine-rich-repeat-kinase 2 (LRRK2), the causative gene for PARK8 type PD with autosomal dominant inheritance, are the most prevalent genetic causes of both familial and sporadic PD.
Together, our results suggest the relevance of mitochondrial-associated pathway in LRRK2 and parkin-related pathogenesis, and that AMPK activation may represent a potential therapeutic strategy for these familial forms of PD.
Human genetics studies have linked LRRK2 as a major genetic contributor to familial and sporadic Parkinson's disease (PD), a neurodegenerative movement disorder that inflicts millions worldwide.
LRRK2 mutations cause late-onset familial PD with a clinical, neurochemical and, for the most part, neuropathological phenotype that is indistinguishable from idiopathic PD.
The location of LRRK2 gene on chromosome 12, close to a linkage peak for familial late-onset Alzheimer's Disease (AD), highlights that LRRK2 mutations might be involved in AD pathogenesis.
Therapeutic strategies targeted at modulating Lrrk2 kinase activity may be important to treat patients with genetically defined familial or typical sporadic Parkinson's disease.
We find that expression of familial mutant G2019SLRRK2 does not dramatically elevate the pathological burden of α-synuclein or neurodegeneration in neurons.
Last, mutations in 2 of these genes turned out to be frequent enough to have relevance in clinical practice: parkin mutations are common in early-onset familial and sporadic PD; moreover, emerging data delineate mutations in the LRRK2 gene (encoding the dardarin protein) as a frequent cause of the familial late onset PD forms, and even of few late-onset sporadic cases.
In addition, etiological factors (LRRK2, alpha-synuclein) and risk loci might also combine in this common mechanism, providing a powerful experimental setting to dissect the cause of both familial and idiopathic disease.
To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson's disease.
The identification of mutations in six genes responsible for Mendelian forms of PD; alpha-synuclein (SNCA), parkin (PRKN), ubiquitin C-terminal hydrolase L1 (UCH-L1), oncogene DJ-1, PTEN-induced putative kinase 1 (PINK1), and most recently leucine-rich repeat kinase 2 (LRRK2), has confirmed the role of genetics in familial forms of the disease.
Mutations in the leucine-rich repeat kinase 2 gene are the most frequent cause of familial and sporadic Parkinson's disease, and G2019S is the most common leucine-rich repeat kinase 2 mutation across several Mediterranean countries.
Furthermore, we propose possible intrabody applications against leucine-rich repeat kinase 2 (LRRK2), whose mutations are the most frequent known cause of familial and sporadic PD.