Roles of lysosomotropic agents on LRRK2 activation and Rab10 phosphorylation was written by Kuwahara, Tomoki;Funakawa, Kai;Komori, Tadayuki;Sakurai, Maria;Yoshii, Gen;Eguchi, Tomoya;Fukuda, Mitsunori;Iwatsubo, Takeshi. And the article was included in Neurobiology of Disease in 2020.Computed Properties of C21H26N2S2 This article mentions the following:
Leucine-rich repeat kinase 2 (LRRK2), the major causative gene product of autosomal-dominant Parkinson鈥瞫 disease, is a protein kinase that phosphorylates a subset of Rab GTPases. Since pathogenic LRRK2 mutations increase its ability to phosphorylate Rab GTPases, elucidating the mechanisms of how Rab phosphorylation is regulated by LRRK2 is of great importance. We have previously reported that chloroquine-induced lysosomal stress facilitates LRRK2 phosphorylation of Rab10 to maintain lysosomal homeostasis. Here we reveal that Rab10 phosphorylation by LRRK2 is potently stimulated by treatment of cells with a set of lysosome stressors and clin. used lysosomotropic drugs. These agents commonly promoted the formation of LRRK2-coated enlarged lysosomes and extracellular release of lysosomal enzyme cathepsin B, the latter being dependent on LRRK2 kinase activity. In contrast to the increase in Rab10 phosphorylation, treatment with lysosomotropic drugs did not increase the enzymic activity of LRRK2, as monitored by its autophosphorylation at Ser1292 residue, but rather enhanced the mol. proximity between LRRK2 and its substrate Rab GTPases on the cytosolic surface of lysosomes. Lysosomotropic drug-induced upregulation of Rab10 phosphorylation was likely a downstream event of Rab29 (Rab7L1)-mediated enzymic activation of LRRK2. These results suggest a regulated process of Rab10 phosphorylation by LRRK2 that is associated with lysosomal overload stress, and provide insights into the novel strategies to halt the aberrant upregulation of LRRK2 kinase activity. In the experiment, the researchers used many compounds, for example, 10-(2-(1-Methylpiperidin-2-yl)ethyl)-2-(methylthio)-10H-phenothiazine (cas: 50-52-2Computed Properties of C21H26N2S2).
10-(2-(1-Methylpiperidin-2-yl)ethyl)-2-(methylthio)-10H-phenothiazine (cas: 50-52-2) belongs to piperidine derivatives. The piperidine moiety constitutes an important building block for the synthesis of a variety of bioactive natural products, alkaloids and other drugs. Several piperidine alkaloids isolated from natural herbs, were found to exhibit antiproliferation and antimetastatic effects on various types of cancers both in vitro and in vivo for example Piperine, Evodiamine, Matrine, Berberine and Tetrandine.Computed Properties of C21H26N2S2
Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem