Collectively, these results suggest that LRRK2 could be a potential molecular target for developing therapeutics to treat Mn-related neurodegenerative disorders.
Interestingly, Rab10 is a key substrate of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine protein kinase genetically associated with the second most common neurodegenerative disease Parkinson's disease.
We believe that these findings provide important supplementary information about the regulatory mechanisms by which both variants influence PILRB and LRRK2 gene expression and neurodegenerative disease risk.
Several mutations in leucine rich repeat kinase 2 (LRRK2) gene have been associated with pathogenesis of Parkinson's disease (PD), a neurodegenerative disorder marked by resting tremors, and rigidity, leading to Postural instability.
The aim of this study was to identify new potentially active compounds for three protein targets, tropomyosin receptor kinase A (TrkA), <i>N</i>-methyl-d-aspartate (NMDA) receptor, and leucine-rich repeat kinase 2 (LRRK2), that are related to various neurodegenerative diseases such as Alzheimer's, Parkinson's, and neuropathic pain.
Although the physiological function of LRRK2 protein remains largely elusive, increasing evidence suggests that it plays a role in innate immunity, a process that also has been implicated in neurodegenerative diseases, including PD.
Four of these validated variants were nonsense mutations, six were observed in genes directly or indirectly related to neurodegenerative disorders (NDs), such as LPA, LRRK2, and FGF20.
Our results revealed clinical heterogeneity of the LRRK2p.I2012T substitution, and demonstrated the use of targeted NGS for genetic diagnosis in multiplex families with PD or mixed neurodegenerative disorders.
Since LRRK2 is detected in tau-positive inclusions in brain tissue affected by various neurodegenerative disorders, including PD, LRRK2-stimulated phosphorylation of tau by GSK-3β may be involved in development of pathological features in the initial stage of PD.
Parkinson disease is a progressive neurodegenerative disease for which leucine-rich repeat kinase 2 (LRRK2 carriers) p.G2019S confers substantial genotypic and population attributable risk.
Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most frequent genetic lesions so far found in familial as well as sporadic forms of PD (Parkinson's disease), a neurodegenerative disease characterized by the dysfunction and degeneration of dopaminergic and other neuronal types.
In summary, the effective shRNA against LRRK2 R1441 alleles described herein suggests that RNAi-based therapy of inherited Parkinson's disease is a viable approach towards developing effective therapeutic interventions for this serious neurodegenerative disease.
The pleomorphic features exhibited by LRRK2 mutation carriers and the central role of Lrrk2 protein in the proper functioning of central nervous system suggest that mutations in this protein might be involved in multiple cellular processes leading to other neurodegenerative disorders than PD.
The predicted multifunctionality of LRRK2 product and the pleomorphic pathology associated with LRRK2 mutations place this gene as a potential candidate for other neurodegenerative disorders, mainly Alzheimer's disease (AD).
These findings are significant in that they link LRRK2 with microtubules, a structural component of the cell that is critically involved in the pathogenesis of several neurodegenerative diseases, including PD.
These findings may be coincidental; however, there is a small nucleus of LRRK2-positive patients displaying atypical features suggesting a role for this protein in other neurodegenerative disorders.
Pathogenic Lrrk2Y1699C substitution observed in a large German-Canadian kindred presents a neurodegenerative disorder that is reminiscent of amyotrophic lateral sclerosis and Parkinsonism-Dementia Complex.