Why is this study relevant?
Understanding of the huntingtin protein remains somewhat limited, yet
the majority of HD therapeutics currently being developed arehuntingtin-lowering
therapies, and the potential biological consequences consequences of
lowering wildtype and mutant HTT in humans long-term is unknown. A
greater understanding of huntingtin structure-function could help answer
some of these questions and alleviate anxieties about the implications
of lowering therapies.
The structure of HTT in complex with HAP40 published byGuo et
al laid a tremendous foundation in our understanding of HTT
structure-function. However, many questions remain: is HAP40 a
constitutive binder of HTT? What is the biological relevance of the
HAP40-bound vs apo structures of HTT? By what mechanism does
polyglutamine expansion of the huntingtin protein confer disease
pathology? What is(are) the cellular function(s) of HTT? The work by
Jung et al aims to begin to answer some of these questions with relation
to polyglutamine tract dependency on huntingtin structural biology.