Rebalance of mitophagy by inhibiting LRRK2 improves colon alterations in an MPTP in vivo model

Alessia Filippone; Deborah Mannino; Laura Cucinotta; Fabrizio Calapai; Lelio Crupi; Irene Paterniti; Emanuela Esposito

doi:10.1016/j.isci.2024.110980

Rebalance of mitophagy by inhibiting LRRK2 improves colon alterations in an MPTP in vivo model

iScience. 2024 Sep 16;27(10):110980. doi: 10.1016/j.isci.2024.110980. eCollection 2024 Oct 18.

Authors

Alessia Filippone¹, Deborah Mannino¹, Laura Cucinotta¹, Fabrizio Calapai², Lelio Crupi¹, Irene Paterniti¹, Emanuela Esposito¹

Affiliations

¹ Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31-98166 Messina, Italy.
² Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are common genetic causes of Parkinson's disease (PD). Studies demonstrated that variants in LRRK2 genetically link intestinal disorders to PD. We aimed to evaluate whether the selective inhibitor of LRRK2, PF-06447475 (PF-475), attenuates the PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in central nervous system (CNS) and in the gastrointestinal system. CD1 mice received four intraperitoneal injections of MPTP (20 mg/kg, total dose of 80 mg/kg) at 2 h intervals (day 1). After 24 h PF-475 was administered intraperitoneally at the doses of 2.5, 5, and 10 mg/kg for seven days. LRRK2 inhibition reduced brain α-synuclein and modulated mitophagy pathway and reduced pro-inflammatory markers and α-synuclein aggregates in colonic tissues through the modulation of mitophagy proteins. LRRK2 inhibition suppressed MPTP-induced enteric dopaminergic neuronal injury and protected tight junction in the colon. Results suggested that PF-475 may attenuate gastrointestinal dysfunction associated to PD.

Keywords: Biochemistry; Cell biology; Molecular biology.