A novel pathway in protein aggregation and neurodegenerative disease

For an increasing number of neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease and polyglutamine disease, e.g. Huntington’s disease, the aggregation of misfolded protein is thought to play a crucial role in the neuropathy. Recently, a new gene has been identified in a Caenorhabditis elegans (C.elegans) model for polyglutamine aggregation, called modifier of aggregation 4 (moag-4). Inactivation of moag-4 suppressed aggregation by 75% and reduced polyglutamine toxicity. These effects have been replicated in C.elegans models for aggregation in Alzheimer’s disease and Parkinson’s disease. Moreover, moag-4 has two human orthologues, Serf1a and Serf2, which in cell culture show a similar effect on aggregation and toxicity of mutant huntingtin. It is unknown how moag-4 influences aggregation. We hypothesized that moag-4 acts on aggregation through downstream targets. In order to investigate this, we performed a RNA interference screen, in which we knocked-down selected genes that have been previously associated with protein aggregation and determined whether they could reverse the effect of moag-4 inactivation, what would indicate that moag-4 acts through these genes. We included genes coding for transcription factors of the insulin/IGF-1 signalling pathway, heat shock proteins, components of CCT chaperonin, predicted chaperones, the ubiquitin-proteasome system and C.elegans orthologues of genes associated to aggregation in other species. Knock-down of none of the included genes could rescue the suppression of aggregation by loss-of-function of moag-4. These findings strongly suggest that moag-4 acts independently of genes known to influence protein aggregation in C.elegans and therefore might represent a novel pathway in protein folding and neurodegenerative diseases.