2022年6月11日 · Pathogenic mutations in the LRRK2 gene increase protein kinase activity and represent the most common genetic risk factor for Parkinson’s disease. Importantly, a large body of work has demonstrated that pharmacological inhibition of LRRK2 can limit the detrimental consequences of mutations across a variety of experimental models.

2010年2月11日 · Lrrk2-G2019S protein purified from Tg brains had higher kinase activity than wild-type Lrrk2 (Li et al., 2010). By 18 months of age, dopaminergic neuron number in the substantia nigra remained the same between Tg mice and wild-type controls ( Liu et al., 2022 ).

2020年9月9日 · It is an established phenomenon that some LRRK2 kinase inhibitors can induce a filamentous accumulation of LRRK2 at microtubules (Ramírez et al., 2017; Dzamko et al., 2010) and that this corresponds to changes in the LRRK2 complex, such as the loss of 14-3-3 binding, or the recruitment of phosphatases (Dzamko et al., 2010; Lobbestael et al ...

The G2019S LRRK2 mutation increases lrrk2’s kinase activity, but other pathogenic variants have different effects, including dampening kinase or GTPase activity. Animal and cell culture studies have linked lrrk2’s kinase activity to toxicity, and kinase inhibitors are being pursued as a therapeutic strategy for PD.

2020年4月24日 · Later, LRRK2 variants were found to increase the risk for developing idiopathic forms of the disease as well (Gilks et al., 2005). How its protein predisposes to PD has been debated because it is massive, sporting many different functional domains. In people, LRRK2 is widely expressed but highest in the kidney, lung, and lymph (Biskup et al ...

2024年5月3日 · Human LRRK2 protein was detected predominantly in the ventral midbrain, olfactory bulb, and spinal cord, with lower levels in the cerebral cortex and cerebellum, perhaps due to ectopic Cre recombinase activity. Levels of mouse LRRK2 protein were at or near physiological levels. DAT-LRRK2 mice behaved normally into advanced age.

2018年1月16日 · This is a reasonable initial hypothesis, however, residue G2019 resides precisely in the active site of LRRK2 (based on a homology model) and residue N2081 resides in the distal side of the C-lobe, which is far away from the active site and pointing into the solvent, rendering it unlikely to have any direct effects on the active site or ...

2020年5月20日 · DNL151 is an orally available, brain-penetrant inhibitor of the leucine-rich repeat kinase 2 (LRRK2). It started out as a backup to Denali’s lead LRRK2 inhibitor, DNL201; but it is now its lead candidate after development of DNL201 was stopped in 2020.

2009年6月16日 · LRRK2 R1441C Mice Recapitulate PD Motor Deficits The recent article by C.J. Li’s group reports on the first transgenic LRRK2 mouse model. The LRRK2 mouse uses a BAC system to express WT or R1441C LRRK2, which is a mutation in the GTPase domain of LRRK2.

2024年1月18日 · In the midbrain, Lrrk2 expression was highly co-localized with dopaminergic neurons, that is, neurons co-labeling with tyrosine hydroxylase (TH) (Lee et al., 2015). It is important to note that markers of LRRK2 kinase activity, like pS1292-LRRK2 or phosphorylated Rab proteins, have not yet been established in brain tissue (Andrew West, personal ...