Understanding the relationship between precocious neuronal differentiation and early-onset neurodegeneration

Several common mechanisms have been implicated in neurodegenerative diseases. The accumulation of misfolded proteins, microtubule disruption, mitochondrial dysfunction, upregulation of autophagy, and oxidative stress are all known contributors to neurodegeneration. Because there are currently no effective treatments for neurodegenerative diseases, there is a critical need for developing new model systems to study neurodegenerative mechanisms in order to identify novel therapeutic targets. C. elegans has been used as a genetic model to study neurodegeneration because of its well-defined nervous system and the C. elegans model system enables identification of common mechanisms in neurodegeneration that are conserved across the animal kingdom. This project seeks to identify a novel common mechanism in neurodegeneration that has not been reported before, which is the precocious neuronal differentiation. We model human congenital hydrocephalus associated human Trim71 genetic variants in C. elegans neurons by knocking in the de novo p.Arg608His mutation at a homologous position in the C. elegans lin-41 gene using the CRISPR engineering. lin-41, the C. elegans homolog of Trim71, was identified as a heterochronic gene that coordinates the temporal sequence of cell division and differentiation in many C. elegans cell types and tissues. The created lin-41(xr77) mutant allele, like the human and mouse de novo p.Arg608His mutation in Trim71, causes precocious neuronal differentiation. To our surprise, it additionally exhibits adult stage early-onset neurodegeneration, which has never been reported before. Premature neuronal differentiation in lin-41 mutants results in precociously, yet properly, built neuronal structures, that function normally in young adult stage. Other heterochronic mutations that cause precocious neuronal differentiation, including lin-14 and lin-28 mutant alleles, also result in early-onset neurodegeneration. We reason since neuronal structures in these mutants are built earlier than the normal schedule, they break down earlier, leading to adult stage early-onset neurodegeneration. We thus hypothesize that the timing of neuronal differentiation and the timing of neurodegeneration have a strong relationship in heterochronic mutants. This project aims to determine whether heterochronic perturbations that cause delayed neuronal differentiation result in a delay in normal age-related neurodegeneration. In addition, we will determine whether the heterochronic gene lin-14, like the heterochronic gene lin-41, is required and functions during early development to deter precocious neuronal differentiation, which in turn prevents future adult stage early-onset neurodegeneration.