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.

Grant Number: 5R21AG088400-02
NIH Institute/Center: NIH
Principal Investigator: Chieh Chang