LRRK2 phosphorylation level correlates with abnormal motor behaviour in an experimental model of levodopa-induced dyskinesias.
Mol Brain. 2016-05-11; 9(1):
DOI: 10.1186/s13041-016-0234-2
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Stanic J(1), Mellone M(1), Cirnaru MD(2), Perez-Carrion M(3), Zianni E(1), Di Luca M(1), Gardoni F(4), Piccoli G(2)(3).
Author information:
(1)DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
(2)IN-CNR, Milano, Italy.
(3)Dulbecco Telethon Institute and Center for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
(4)DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Levodopa (L-DOPA)-induced dyskinesias (LIDs) represent the major side effect in
Parkinson’s disease (PD) therapy. Leucine-rich repeat kinase 2 (LRRK2) mutations
account for up to 13 % of familial cases of PD. LRRK2 N-terminal domain
encompasses several serine residues that undergo phosphorylation influencing
LRRK2 function. This work aims at investigating whether LRRK2
phosphorylation/function may be involved in the molecular pathways downstream D1
dopamine receptor leading to LIDs. Here we show that LRRK2 phosphorylation level
at serine 935 correlates with LIDs induction and that inhibition of LRRK2 induces
a significant increase in the dyskinetic score in L-DOPA treated parkinsonian
animals. Our findings support a close link between LRKK2 functional state and
L-DOPA-induced abnormal motor behaviour and highlight that LRRK2 phosphorylation
level may be implicated in LIDs, calling for novel therapeutic strategies.