Research article

Emerging role of LRRK2 in human neural progenitor cell cycle progression, survival and differentiation

Javorina Milosevic^1,2 , Sigrid C Schwarz² , Vera Ogunlade³ , Anne K Meyer⁴ , Alexander Storch^4,5 and Johannes Schwarz²

¹  Translational Centre for Regenerative Medicine – Leipzig (TRM-Leipzig), University of Leipzig, Philipp-Rosenthal-Straße 55, 04103 Leipzig, Germany

²  Department of Neurology, University of Leipzig, Liebigstr. 22a, 04103, Germany

³  Department of Neuropathology, University of Leipzig, 04103 Leipzig, Germany

⁴  Department of Neurology, Dresden University of Technology, 01307 Dresden, Germany

⁵  Center for Regenerative Therapies Dresden, Dresden University of Technology, 01307 Dresden, Germany

author email corresponding author email

Molecular Neurodegeneration 2009, 4:25doi:10.1186/1750-1326-4-25

Published:	15 June 2009

Abstract

Despite a comprehensive mapping of the Parkinson's disease (PD)-related mRNA and protein leucine-rich repeat kinase 2 (LRRK2) in the mammalian brain, its physiological function in healthy individuals remains enigmatic. Based on its structural features and kinase properties, LRRK2 may interact with other proteins involved in signalling pathways. Here, we show a widespread LRRK2 mRNA and/or protein expression in expanded or differentiated human mesencephalic neural progenitor cells (hmNPCs) and in post-mortem substantia nigra PD patients. Using small interfering RNA duplexes targeting LRRK2 in hmNPCs following their differentiation into glia and neurons, we observed a reduced number of dopaminergic neurons due to apoptosis in LRRK2 knockdown samples. LRRK2-deficient hmNPCs exhibited elevated cell cycle- and cell death-related markers. In conclusion, a reduction of LRRK2 expression in hmNPCs severely impaired dopaminergic differentiation and/or survival of dopaminergic neurons most likely via preserving or reactivating the cell cycle.