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Hum Mol Genet. 2016 Feb 15;25(4):672-80. doi: 10.1093/hmg/ddv504. Epub 2016 Jan 6.

Synphilin-1 attenuates mutant LRRK2-induced neurodegeneration in Parkinson's disease models.

Author information

1
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA.
2
Division of Neurobiology, Department of Psychiatry.
3
Department of Pharmacology, The B. Rappaport Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel.
4
Division of Neurobiology, Department of Psychiatry, Departments of Neuroscience, Neurology, and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA and wsmith@rx.umaryland.edu caross@jhu.edu.
5
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA, wsmith@rx.umaryland.edu caross@jhu.edu.

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant Parkinsonism with pleomorphic pathology including deposits of aggregated protein and neuronal degeneration. The pathogenesis of LRRK2-linked Parkinson's disease (PD) is not fully understood. Here, using co-immunoprecipitation, we found that LRRK2 interacted with synphilin-1 (SP1), a cytoplasmic protein that interacts with α-synuclein and has implications in PD pathogenesis. LRRK2 interacted with the N-terminus of SP1 whereas SP1 predominantly interacted with the C-terminus of LRRK2, including kinase domain. Co-expression of SP1 with LRRK2 increased LRRK2-induced cytoplasmic aggregation in cultured cells. Moreover, SP1 also attenuated mutant LRRK2-induced toxicity and reduced LRRK2 kinase activity in cultured cells. Knockdown of SP1 by siRNA enhanced LRRK2 neuronal toxicity. In vivo Drosophila studies, co-expression of SP1 and mutant G2019S-LRRK2 in double transgenic Drosophila increased survival and improved locomotor activity. Expression of SP1 protects against G2019S-LRRK2-induced dopamine neuron loss and reduced LRRK2 phosphorylation in double transgenic fly brains. Our findings demonstrate that SP1 attenuates mutant LRRK2-induced PD-like phenotypes and plays a neural protective role.

PMID:
26744328
PMCID:
PMC4743687
DOI:
10.1093/hmg/ddv504
[Indexed for MEDLINE]
Free PMC Article

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