How do LRRK2 inhibitors work?
Recent work has revealed that LRRK2 inhibits basal mitophagy in a variety of cells including dopaminergic neurons and that LRRK2 inhibitors promote mitophagy in LRRK2[G2019S] knock-in mice [25]. LRRK2 has also been shown to control repair of damaged endomembranes through its ability to phosphorylate Rab8A [26,27].
How does LRRK2 cause Parkinsons?
Parkinson’s disease (PD)-linked familial mutations in LRRK2 impact its enzymatic activity by commonly increasing kinase activity, either directly within the kinase domain or indirectly via the GTPase domain by impairing GTP hydrolysis.
What is G2019S?
The LRRK2 G2019S mutation is the most common genetic determinant of Parkinson’s disease (PD) identified to date. This mutation, reported in both familial and sporadic PD, occurs at elevated frequencies in Maghreb population.
What is the function of SNCA?
Normal Function The SNCA gene provides instructions for making a small protein called alpha-synuclein. Alpha-synuclein is abundant in the brain, and smaller amounts are found in the heart, muscles, and other tissues.
What does SNCA stand for?
SNCA (Synuclein Alpha) is a Protein Coding gene. Diseases associated with SNCA include Dementia, Lewy Body and Parkinson Disease 1, Autosomal Dominant.
What are LRRK2 inhibitors?
Treatment for or prevention of Intestinal Bowel Disorders. A LRRK2 inhibitor would be a unique form of anti-inflammatory therapy that will complement or compete with an array of cytokines in primary treatment for lBD. A LRRK2 inhibitor would provide a much needed alternate mode of therapy.
How does LRRK2 kinase regulate synaptic morphology?
Lee S., Liu H.P., Lin W.Y., Guo H., Lu B. LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction. J. Neurosci. 2010;30(50):16959–16969. doi: 10.1523/JNEUROSCI.1807-10.2010.
What happens to type II pneumocytes when LRRK2 is blocked?
In the alveolus, type II pneumocytes secrete surfactants that facilitate the diffusion of oxygen into the blood. When LRRK2 is blocked, they develop cytoplasmic vacuoles. [Courtesy of Katherinebutler1331 – Own work, CC BY-SA 4.0 .]
Is lrrk2-in1 a brain penetrant?
The very first LRRK2 specific compound published allowed the confirmation of cellular and in vivophosphorylation changes in LRRK2. LRRK2-IN1 was found to be active in peripheral tissues, but is not brain penetrant [77].