User:Estelle Metzger/Sandbox

One of the way to try to treat the Parkinson’s disease is focused around LRRK2. Indeed, mutations in LRRK2, which increses its kinase activity, are found in case of Parkinson’s disease. Thus, a kinase inhibitor for LRRK2 would be an interesting thetapeutic target.

Thanks to the similarity between LRRK2 and Roco4 from the Dictyostelium, Roco4 is used in studies that aims at finding that inhibitor. One the candidates to inhibit this activity is LRRK2-IN-1.

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Humanized Roco4

Parler des domaines Des 2 mutations

Manque : structure info ect sur Roco4

LRRK2-IN-1

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Humanized Roco4 and LRRK2-IN-1 interaction

Relevance

LRRK2, for leucine-rich repeat serin/thereonin kinase 2, is a protein from the Roco family of G-proteins. It takes part in divers pathway such as synaptic vesicule trafficking, retrograde trafficking pathway for recycling protein or the CaMKK/AMPK pathway. Its importance comes from the fact that its susspetced to have a role in the phosphorylation of a central protein in the Parkinson’s disease. (Uniprot) Indeed, mutation associated with Parkinson Disease can be found in asmost every domains of LRRK2. For techrapeutic research Rocco4 from the Dictyostelium was mutated, especially in the active site, in order to mime LRRK2. (B. K. Gilsbach, Journal of medicinal chemistry, 2015)

Disease

The Parkinson’s disease (PD) is a neurodegenerative disorder that is associated with resting termor, bradykinesia, rigidity and postural instability. (Uniprot) This is the second most common neurodegenerative disorder, which is affecting 2% of the population above 65 years. (B. K. Gilsbach, Journal of medicinal chemistry, 2015) Two types of Parkinson’s disease existe, the heditary or the sporadic also called idiopathic. LRRK2 mutations can be found in almost its every domains for both types. The most important mutation is the G2019S, which is located on the kinase domain. It stabilise the domains, thus leading to an indresed kinase activity of 2 to 4 fold. That’s why a treatment stategy would be to develop a kinase inhibitor in order to counter it. (B. K. Gilsbach, Journal of medicinal chemistry, 2015) The use of roco4, permited to learn that the G2019S mutation is the results of an additional hydrogen bound between Ser2019 ( Ser1179 in Roco4) and Gln1918 (Arg1077 in Roco4). (B. K. Gilsbach, Journal of medicinal chemistry, 2015)