We discuss the roles of heterozygous LRRK2 mutations and heterozygous parkin and PINK1 mutations in the development of parkinsonism, and propose an integrated aetiological model for this complex disease.
In this brain bank-based series, LRRK2G2019S mutation occurred in patients with parkinsonism associated with either typical brainstem LB pathology or non-specific nigral degeneration.
Here, we used a two-step approach to identify compounds from the FDA-approved licensed drug library that could suppress neurite degeneration in LRRK2-G2019Sparkinsonism.
We conducted PET of 2 subjects and neuropathologically examined 8 subjects in the same family from the Sagamihara district, the original source of PARK8-linked parkinsonism (I2020T mutation).
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as a much more common cause for dominant PS, especially in certain ethnic groups, while mutations in the parkin gene, in DJ-1, PINK1 and ATP13A2 cause autosomal recessive parkinsonism of early onset.
Therefore, the LRRK2 mutation has a relatively high frequency in the AJ population, is not fully penetrant for parkinsonism in the elderly, and does not appear to be commonly associated with late-onset dementia.
We have identified Family SK where Lrrk2G2019S segregates with slowly progressive parkinsonism and the affected proband has tau-immunopositive neurofibrillary tangle pathology.
Leucine-rich repeat kinase 2 (LRRK2) mutation is the most common cause of genetic-related parkinsonism and is usually associated with Lewy body pathology; however, tau, α-synuclein, and ubiquitin pathologies have also been reported.
However we can not rule out other genetic variation at the LRRK2 locus may play a role in parkinsonian disorders with amyotrophic lateral sclerosis and may be considered candidates for genetic screening.
Leucine-rich repeat kinase 2 (LRRK2) mutation carriers can develop clinical symptoms other than typical parkinsonism such as dementia, amyotrophy or dystonia.
Several kinases have been implicated in the pathogenesis of Parkinson's disease (PD), most notably leucine-rich repeat kinase 2 (LRRK2), as LRRK2 mutations are the most common genetic cause of a late-onset parkinsonism that is clinically indistinguishable from sporadic PD.
Moreover, mutations in LRRK2 known to cause parkinsonism are associated not only with dopaminergic neuronal degeneration, but also with the accumulation of synuclein, tau, neither, or both proteins.