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New light on the mechanism of Parkinson’s disease

01 September 2010 Biochemical Society, The

A significant number of Parkinson’s disease patients have a mutation of the enzyme Leucine-Rich Repeat Protein Kinase 2 (LRRK2, also known as dardarin).

However, little is understood about how it is regulated or functions. In a new paper in the Signal Knowledge Environment of the Biochemical Journal, Dario Alessi and colleagues from the University of Dundee demonstrate that a family of proteins, the 14-3-3 proteins, interact with LRRK2.

Mutations of the gene responsible for expressing LRRK2 have been linked to an increased risk of Parkinson’s and Crohn’s diseases; the researchers found that five of the six most common pathogenic mutations of LRRK2 affect its ability to bind with 14-3-3 proteins and alter cellular localization – but not kinase activity – of LRRK2. The mutated forms of LRRK2 that fail to bind 14-3-3 proteins accumulate within discrete cytoplasmic pools perhaps resembling inclusion bodies that contain misfolded protein that may be related to the pathology.

This clearer understanding of how LRRK2 is regulated is likely to open promising avenues to Parkinson’s disease researchers.

Professor Mark Lemmon, Deputy Chair for BJ Signal, commented that “although this work shows that understanding LRRK2 mutations is definitely not simple, the Alessi group has discovered important new aspects of LRRK2 regulation that help enormously in thinking about what might be going wrong. The path opened up by this study will be very illuminating for understanding LRRK2 itself, which has been something of an enigma, and its role in Parkinson’s disease.”

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