Study investigates how one common variation in genetics can increase the risk of sporadic Parkinson’s

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Work with OPDC from a DPhil project supported by the Oxford branch of Parkinson’s UK has been published in the journal Stem Cell Reports. The project, carried out under the supervision of OPDC’s Richard Wade-Martins focussed on the MAPT (microtubule-associated protein tau) gene, which provides the code for a set of six proteins called ‘tau’, and each of these six tau proteins is made from a different messenger RNA transcript made from the MAPT gene.  Of the two normal versions of the MAPT gene, one is overrepresented in people with Parkinson’s.

We looked at how small differences between the two normal versions of the MAPT gene change the way the MAPT gene makes the six messenger RNA transcripts and six tau proteins.  We found that the version of the MAPT gene that is overrepresented in Parkinson’s drives the production of more messenger RNA transcripts overall than the other version of the gene.  It also makes different amounts of some of the six specific messenger RNA transcripts.

We then looked at what the function of those specific transcripts may be in the important brain cells (neurons) that die in Parkinson’s, to try and understand how the common genetic differences in MAPT could affect the way neurons function.  Using skin cells from human donors to generate stem cells that keep multiplying, we turned them into the kind of neurons that die in Parkinson’s for study.

The different tau proteins had different effects on transportation within neurons.  Our study suggests that the version of the MAPT gene that is overrepresented in Parkinson’s may cause transportation to slow down in the kind of neurons that die in Parkinson’s.  This slower transportation may then explain why people with this version of the MAPT gene have a greater chance of developing Parkinson’s.

Overall, this study has helped to further our understanding of how common variation in our genomes connects to risk for Parkinson’s.  By understanding what is happening with the different variants of the MAPT gene we know more about the role of the MAPT gene and the tau proteins in normal neuron function and disease.

Beevers JE, Lai MC, Collins E, Booth HDE, Zambon F, Parkkinen L, Vowles J, Cowley SA, Wade-Martins R, Caffrey TM (2017) MAPT Genetic Variation and Neuronal Maturity Alter Isoform Expression Affecting Axonal Transport in iPSC-Derived Dopamine Neurons. Stem Cell Reports. 9(2):587-599. PMID: 28689993