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LRRK2 Dephosphorylation increases its ubiquitination.

Activating mutations in the LRRK2 gene are the most common cause of inherited Parkinson’s disease (PD). LRRK2 is phosphorylated on a cluster of phosphosites including Ser910, 935, 955 and 973, which are dephosphorylated in several PD-related LRRK2 mutants [N1347H, R1441C/G, Y1699C and I2020T] linking the regulation of these sites to PD. These serine residues are also dephosphorylated after kinase inhibition and lose 14-3-3 binding, which serve as pharmacodynamic markers for inhibited LRRK2. Loss of 14-3-3 binding is well established, but the consequences of dephosphorylation are only now being uncovered. In the present study, we found that potent and selective inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser935 then ubiquitination and degradation of a significant fraction of LRRK2. GNE1023 treatment decreased the phosphorylation and stability of LRRK2 in expression systems and endogenous LRRK2 in A549 cells and in mouse dosing studies. We next established that LRRK2 is ubiquitinated through at least K48 and K63 ubiquitin linkages in response to inhibition. To investigate the link between dephosphorylation induced by inhibitor treatment and LRRK2 ubiquitination, we studied LRRK2 in conditions where it is dephosphorylated such as expression of PD mutants [R1441G, Y1699C and I2020T] or by blocking 14-3-3 binding to LRRK2 via difopein expression, and found LRRK2 is hyper-ubiquitinated. Calyculin A treatment prevents inhibitor and PD mutant induced dephosphorylation and reverts LRRK2 to a lesser ubiquitinated species, thus directly implicating phosphatase activity in LRRK2 ubiquitination. This dynamic dephosphorylation-ubiquitination cycle could explain detrimental loss of function phenotypes found in peripheral tissues of LRRK2 kinase inactive mutants, LRRK2 KO animals and following LRRK2 inhibitor administration.

Autoren:   Zhao J; Molitor T; Langston J; Nichols R
Journal:   Biochemical Journal
Jahrgang:   2015
DOI:   10.1042/BJ20141305
Erscheinungsdatum:   05.05.2015
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