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Neurodegenerative disease

Common routes to risk

Nature Reviews Neuroscience volume 14, pages 228–229 (2013)Cite this article

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The authors conducted global phenotype impact analyses to assess the effects of seven PD risk-associated variants on gene transcription in the brains of unaffected carriers. They found that there was a marked overlap between the transcriptome alterations linked to these variants, with the most similar effects being associated with the risk loci PARK16 and LRRK2. Moreover, these two variants showed strong epistasis — that is, the presence or absence of one risk variant modified the effect of the other.

One of the genes found within the PARK16 locus is RAB7L1, which encodes a GTPase that localizes to the Golgi apparatus and has been implicated in protein sorting. The authors showed that LRRK2 and RAB7L1 co-immunoprecipitated and localized to overlapping compartments in transfected cells, suggesting that these proteins interact. Moreover, overexpression of wild-type RAB7L1 suppressed the effects of mutant LRRK2 on rat neuron neurite length in an in vitro screen and on mortality and dopamine neuron survival in a Drosophila melanogaster model.

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ORIGINAL RESEARCH PAPER

  1. MacLeod, D. A. et al. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk. Neuron 77, 425–439 (2013)

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  1. Rachel Jones
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Jones, R. Common routes to risk. Nat Rev Neurosci 14, 228–229 (2013). https://doi.org/10.1038/nrn3467

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