Probiotic<i> Bacillus subtilis</i> protects against α-synuclein aggregation in <i>C. elegans</i>

How the gut microbiome affects Parkinson's disease remains unclear. Goya et al. show that the probiotic B. subtilis strain PXN21 inhibits and clears α-synuclein aggregation in a C. elegans model. The bacterium acts via metabolites and biofilm formation to activate protective pathways in the host, including DAF-16/FOXO and sphingolipid metabolism.Fil: Goya, María Eugenia. University of Edinburgh; Reino UnidoFil: Xue, Feng. University of Edinburgh; Reino UnidoFil: Sampedro Torres Quevedo, Cristina. University of Edinburgh; Reino UnidoFil: Arnaouteli, Sofia. University Of Dundee; Reino UnidoFil: Riquelme Dominguez, Lourdes. University of Edinburgh; Reino UnidoFil: Romanowski, Andrés. University of Edinburgh; Reino Unido. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Brydon, Jack. University of Edinburgh; Reino UnidoFil: Ball, Kathryn L.. University of Edinburgh; Reino UnidoFil: Stanley-Wall, Nicola R.. University Of Dundee; Reino UnidoFil: Doitsidou, Maria. University of Edinburgh; Reino Unid

Trip with TRP: CNI-1 and SEC-24.2 act as TRP-4 channel trafficking regulators in Caenorhabditis elegans

Transient Receptor Potential (TRP) channels are conserved across phylogeny and function as polymodal cellular sensors. Numerous mutations have been shown to affect TRP channel function, causing inherited channelopathies, which include an expanding group of neurological disorders. Furthermore, the role of TRP channels in calcium signalling and homeostasis has implicated them in neurodegenerative diseases, including Parkinson’s. Here, I have used a model of dopaminergic degeneration in Caenorhabditis elegans, in which a dominant mutation in a TRP channel, TRP-4, results in a hyperactive channel state. Consequently, this mutation leads to a progressive and robust loss of dopaminergic neurons. Gain-of-function mutations in ion channels with easily detectable phenotypes such as neurodegeneration, offer a unique opportunity to identify neuroprotective genes, including regulators of channel function. A forward genetic screen for suppressors of TRP-4-induced dopaminergic loss resulted in a collection of mutant strains that show neuroprotection. In my project, I characterise protective mutations that affect components of the secretory pathway. Specifically, I identified a nonsense and a missense allele of cni-1, the only Cornichon ortholog in C. elegans. CNI-1 is a cargo receptor that couples specific membrane proteins to the COPII vesicle-coat, regulating their export from the ER. In addition, I recovered two viable missense mutations in the gene encoding the COPII coat adapter SEC-24.2, which act in a dominant manner to suppress neurodegeneration. I found that the above mutations alter TRP-4 channel trafficking, increasing the amount present at the axons and cell bodies, and impairing its localization to the cilium. Finally, I show that the interaction between the components of the secretory pathway and TRP-4 is conserved in one other member of the TRP channel superfamily, PKD-2. The identified mutations reveal potential interaction points between the TRP cargo, the cargo receptor CNI-1 and SEC-24.2. Overall, these results indicate that the trafficking of TRP-4 is regulated by a two-component ER-export mechanism, which may also be relevant for regulating trafficking of other members of the TRP channel family