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Effects of high-risk Parkinson’s mutation may be reversible

Researchers from the University of Sheffield have found vital new evidence on how to target and reverse the effects caused by one of the most common genetic causes of Parkinson’s.

Mutations in a gene called LRRK2 carry a well-established risk for Parkinson’s disease, although the basis for this link is unclear.

The team, led by Parkinson’s UK funded researchers Dr Kurt De Vos from the Department of Neuroscience and Dr Alex Whitworth from the Department of Biomedical Sciences, found that certain drugs could fully restore movement problems observed in fruit flies carrying the LRRK2 Roc-COR Parkinson’s mutation.

These drugs, deacetylase inhibitors, target the transport system and reverse the defects caused by the faulty LRRK2 within nerve cells. The study was published on 15 October 2014 in Nature Communications.

The LRRK2 gene produces a protein that affects many processes in the cell. It is known to bind to the microtubules, the cells’ transport tracks. A defect in this transport system has been suggested to contribute to Parkinson’s disease. The researchers have investigated this link and have now found the evidence that certain LRRK2 mutations affect transport in nerve cells which leads to movement problems observed in the fruit fly (Drosophila).

The team then used several approaches to show that preventing the association of the mutant LRRK2 protein with the microtubule transport system rescues the transport defects in nerve cells, as well as the movement deficits in fruit flies.

Dr De Vos said: “We successfully used drugs called deacetylase inhibitors to increase the acetylated form of α-tubulin within microtubules which does not associate with the mutant LRRK2 protein. We found that increasing microtubule acetylation had a direct impact on cellular axonal transport.

 

Journal Reference:

Vinay K. Godena, Nicholas Brookes-Hocking, Annekathrin Moller, Gary Shaw, Matthew Oswald, Rosa M. Sancho, Christopher C. J. Miller, Alexander J. Whitworth, Kurt J. De Vos. Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutationsNature Communications, 2014; 5: 5245 DOI: 10.1038/ncomms6245

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