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. 2006 Nov;60(5):557-569.
doi: 10.1002/ana.21019.

Localization of LRRK2 to membranous and vesicular structures in mammalian brain

Saskia Biskup  1   2 , Darren J Moore  1   2 , Fulvio Celsi  3 , Shinji Higashi  4   5 , Andrew B West  1   2 , Shaida A Andrabi  1   2 , Kaisa Kurkinen  1   2 , Seong-Woon Yu  1   2 , Joseph M Savitt  1   2 , Henry J Waldvogel  6 , Richard L M Faull  6 , Piers C Emson  5 , Reidun Torp  3 , Ole P Ottersen  3 , Ted M Dawson  1   2   7 , Valina L Dawson  1   2   7   8
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Localization of LRRK2 to membranous and vesicular structures in mammalian brain

Saskia Biskup et al. Ann Neurol. 2006 Nov.

Abstract

Objective: The PARK8 gene responsible for late-onset autosomal dominant Parkinson's disease encodes a large novel protein of unknown biological function termed leucine-rich repeat kinase 2 (LRRK2). The studies herein explore the localization of LRRK2 in the mammalian brain.

Methods: Polyclonal antibodies generated against the amino or carboxy termini of LRRK2 were used to examine the biochemical, subcellular, and immunohistochemical distribution of LRRK2.

Results: LRRK2 is detected in rat brain as an approximate 280kDa protein by Western blot analysis. Subcellular fractionation demonstrates the presence of LRRK2 in microsomal, synaptic vesicle-enriched and synaptosomal cytosolic fractions from rat brain, as well as the mitochondrial outer membrane. Immunohistochemical analysis of rat and human brain tissue and primary rat cortical neurons, with LRRK2-specific antibodies, shows widespread neuronal-specific labeling localized exclusively to punctate structures within perikarya, dendrites, and axons. Confocal colocalization analysis of primary cortical neurons shows partial yet significant overlap of LRRK2 immunoreactivity with markers specific for mitochondria and lysosomes. Furthermore, ultrastructural analysis in rodent basal ganglia detects LRRK2 immunoreactivity associated with membranous and vesicular intracellular structures, including lysosomes, endosomes, transport vesicles, and mitochondria.

Interpretation: The association of LRRK2 with a variety of membrane and vesicular structures, membrane-bound organelles, and microtubules suggests an affinity of LRRK2 for lipids or lipid-associated proteins and may suggest a potential role in the biogenesis and/or regulation of vesicular and membranous intracellular structures within the mammalian brain.

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References

    1. Funayama M, Hasegawa K, Kowa H, et al. A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 2002; 51: 296-301.
    1. Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 2004; 44: 595-600.
    1. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004; 44: 601-607.
    1. Moore DJ, West AB, Dawson VL, Dawson TM. Molecular pathophysiology of Parkinson's disease. Annu Rev Neurosci 2005; 28: 57-87.
    1. West AB, Moore DJ, Biskup S, et al. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A 2005; 102: 16842-16847.

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