Distinct Huntingtin’s protein aggregates differently impact viability and motility in C. elegans

A broad range of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's
disease (PD), and Huntington's disease (HD), are associated with the aggregation of proteins
into amyloid fibrils. For many amyloid-forming proteins, the aggregation process proceeds
through a complex mixture of intermediates predominately comprising oligomers. Due to thecomplex heterogeneity associated with amyloid formation, it is difficult to assign specific toxic
functions to different aggregate species, particularly when expressing aggregating proteins within
cells or organisms. To overcome this challenge, a mutant Huntington protein [htt-exon1(46Q)],
which readily aggregates and is associated with HD, was employed as a model system to
create a protocol that exposes the N2 strain of C. elegans to well-characterized, specific
aggregates to assess toxicity. Viause of controlled aggregation conditions and separation
techniques, uniform populations of htt-exon1 (46Q) aggregates were obtained and characterized
using atomic force microscopy and dynamic light scattering. Upon exposure to these different
aggregate populations, the viability and motility of C. elegans were determined. Htt-
exon1 (46Q) oligomers represented the most potently toxic aggregate form. Fibrils did not invoke
any toxicity in N2 worms; however, exposure of C. elegans resulting in them expressing a nonpathogenic htt
fragment that does not aggregate results of reduced viability. To demonstrate the utility of this
approach, several additional experiments were performed with oligomers. First, chemically
cross-linking htt-exon1 (46Q) oligomers and stabilizing oligomers
via the incorporation of truncated small peptides derived from the first 17 amino acids of
Huntington's disease induced toxicity differently. These representative methods of controlling the type of aggregate species introduced into a living system to assess toxicity and methods that alter that toxicity are discussed.