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Mov Disord. 2017 Mar;32(3):423-432. doi: 10.1002/mds.26892. Epub 2016 Dec 2.

LRRK2 levels and phosphorylation in Parkinson's disease brain and cases with restricted Lewy bodies.

Author information

1
School of Medical Sciences, University of New South Wales, Kensington, Australia.
2
Neuroscience Research Australia, Randwick, Australia.
3
Queen Square Brain Bank, UCL Institute of Neurology, University College London, London, UK.
4
Parkinson's Institute and Clinical Center, Sunnyvale, California, USA.
5
Department of Neuropathology, Brain Bank for Aging Research, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan.
6
Department of Neurology, Saitama Medical University, International Medical Centre, Saitama, Japan.
7
Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands.

Abstract

BACKGROUND:

Leucine rich repeat kinase 2 (LRRK2) is a promising target for the treatment of Parkinson's disease; however, little is known about the expression of LRRK2 in human brain and if/how LRRK2 protein levels are altered in Parkinson's disease.

OBJECTIVES:

We measured the protein levels of LRRK2 as well as its phosphorylation on serines 910, 935, and 973 in the postmortem brain tissue of Parkinson's disease patients and aged controls with and without Lewy bodies.

METHODS:

LRRK2 and its phosphorylation were measured by immunoblot in brain regions differentially affected in Parkinson's disease (n = 30) as well as subjects with Lewy bodies restricted to the periphery and lower brain stem (n = 25) and matched controls without pathology (n = 25).

RESULTS:

LRRK2 levels were increased in cases with restricted Lewy bodies, with a 30% increase measured in the substantia nigra. In clinical Parkinson's disease, levels of LRRK2 negatively correlated to disease duration and were comparable with controls. LRRK2 phosphorylation, however, particularly at serine 935, was reduced with clinical Parkinson's disease with a 36% reduction measured in the substantia nigra.

CONCLUSIONS:

Our data show that LRRK2 phosphorylation is reduced with clinical PD, whereas LRRK2 expression is increased in early potential prodromal stages. These results contribute to a better understanding of the role of LRRK2 in idiopathic Parkinson's disease and may aid efforts aimed at therapeutically targeting the LRRK2 protein. © 2016 International Parkinson and Movement Disorder Society.

KEYWORDS:

Lewy body; Parkinson's disease; brain; phosphorylation; α-synuclein

PMID:
27911006
DOI:
10.1002/mds.26892
[Indexed for MEDLINE]

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