Imagine you’re searching for treasure in a vast field, but you don’t know exactly what you’re looking for. That’s a bit like Parkinson’s disease (PD) researchers trying to find the underlying causes of this neurodegenerative disorder. In this study, scientists used a tiny worm called Caenorhabditis elegans as their treasure-hunting partner. They created a special PD model in these worms and screened over 100 PD genes to see how they affected the development of toxic protein clumps associated with PD. They discovered that inactivating certain worm genes altered the formation of these clumps and even improved neuronal health. The findings suggest that these genes could be potential therapeutic targets for PD or other age-related diseases. But the treasure hunt didn’t stop there! The researchers also found that some of these genes were involved in cellular proteotoxicity, a process linked to protein misfolding and aggregation. This opens up new doors for exploring how these genes might contribute to PD and other neurodegenerative disorders. If you’re curious about the details of this fascinating study, make sure to check out the link below!

Idiopathic Parkinson’s disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons during aging. The pathological hallmark of PD is the Lewy body detected in postmortem brain tissue, which is mainly composed of aggregated α-Synuclein (αSyn). However, it is estimated that 90% of PD cases have unknown pathogenetic triggers. Here, we generated a new transgenic Caenorhabditis elegans PD model eraIs1 expressing green fluorescent protein- (GFP-) based reporter of human αSyn in DA neurons, and exhibited a nice readout of the developed αSyn inclusions in DA neurons, leading to their degeneration during aging. Using these animals in a preliminary reverse genetic screening of >100-PD genome-wide association study- (GWAS-) based susceptibility genes, we identified 28 orthologs of C. elegans and their inactivation altered the phenotype of eraIs1; 10 knockdowns exhibited reduced penetrance of αSyn:Venus inclusions formed in the axons of cephalic (CEP) DA neurons, 18 knockdowns exhibited increased penetrance of disrupted CEP dendrite integrity among which nine knockdowns also exhibited disrupted neuronal morphology independent of the expressed αSyn reporter. Loss-of-function alleles of the five identified genes, such as sac-2, rig-6 or lfe-2, unc-43, and nsf-1, modulated the corresponding eraIs1 phenotype, respectively, and supported the RNA interference (RNAi) data. The Western blot analysis showed that the levels of insoluble αSyn:Venus were not correlated with the observed phenotypes in these mutants. However, RNAi of 12 identified modulators reduced the formation of pro-aggregating polyglutamine Q40:YFP foci in muscle cells, suggesting the possible role of these genes in cellular proteotoxicity. Therefore, modulators identified by their associated biological pathways, such as calcium signaling or vesicular trafficking, represent new potential therapeutic targets for neurodegenerative proteopathies and other diseases associated with aging.

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