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

Javorina Milosevic,Vera Ogunlade,Sigrid C Schwarz,Anne K Meyer,Alexander Storch,Johannes Schwarz

doi:10.1186/1750-1326-4-25

Javorina Milosevic, Vera Ogunlade + Show 4 more

Open Access

https://doi.org/10.1186/1750-1326-4-25

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Journal: Molecular Neurodegeneration	Publication Date: Jan 1, 2009
Citations: 75	License type: cc-by

Affiliation: Leipzig University, TU Dresden

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.

Highlights

The pathology of Parkinson's disease (PD) involves the loss of dopaminergic neurons (DNs) in the substantia nigra and the presence of intraneuronal accumulations of aggregated proteins (Lewy bodies) in surviving neurons
leucine-rich repeat kinase 2 (LRRK2) expression in neural progenitors and PD substantia nigra In order to explore LRRK2 protein expression in human midbrain-derived neural progenitor cells (NPCs), we selected an antibody according to a comprehensive characterization of various LRRK2 antibodies [12]
LRRK2 protein expression was examined in several human mesencephalic neural progenitor cells (hmNPCs) preparations that were cultured for various time periods. 80–95% of these proliferating cells that expressed the NPC marker nestin were immunoreactive for LRRK2 protein (Fig. 1A–C)

Summary

Introduction

The pathology of Parkinson's disease (PD) involves the loss of dopaminergic neurons (DNs) in the substantia nigra and the presence of intraneuronal accumulations of aggregated proteins (Lewy bodies) in surviving neurons. Most PD cases appear to be sporadic. Mutations in the leucine-rich repeat kinase 2 (LRRK2, PARK8) gene are the most common cause of both autosomal-dominant familial and sporadic late-onset cases of PD identified so far [2]. LRRK2 encodes for dardarin, a large and complex protein with an approximate molecular weight of 286 kDa that comprises multiple domains, including leucine-rich repeat (LRR), ROC-COR GTPase, mitogen-activated protein kinase kinase kinase (MAPKKK) and WD40 domains [3,4]. These functional domains support a role in cellular signalling. The most common mutation, G2019S within (page number not for citation purposes)

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