title: LRRK2 phosphorylation level correlates with abnormal motor behaviour in an experimental model of levodopa-induced dyskinesias.
abstract: 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.
authors.affiliation: DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stanic
authors.affiliation: DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Mellone
authors.affiliation: IN-CNR, Milano, Italy.
authors.forename: Maria Daniela
authors.initials: MD
authors.lastname: Cirnaru
authors.affiliation: Dulbecco Telethon Institute and Center for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Perez-Carrion
authors.affiliation: DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Zianni
authors.affiliation: DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Di Luca
authors.affiliation: DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy. fabrizio.gardoni@unimi.it.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
authors.affiliation: IN-CNR, Milano, Italy.|Dulbecco Telethon Institute and Center for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Piccoli
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D020820:Dyskinesias / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007980:Levodopa; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D010300:Parkinson Disease / Q000201:enzymology / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017207:Rats, Sprague-Dawley
chemical_list: D047428:Protein Kinase Inhibitors; D007980:Levodopa; D016627:Oxidopamine; C547428:LRRK2 protein, rat; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
keywords: 6-OHDA; L-DOPA; L-DOPA-induced dyskinesias; LRRK2; Parkinson’s disease; Phosphorylation; Rat