Neurospecific Protein Key to Brain Degeneration in Huntington’s
Although the gene responsible for Huntington’s disease (HD), a dominantly inherited neurodegenerative disorder, was detected more than 10 years ago, the mechanism of its brain-specific pathology has remained elusive. Now investigators at Johns Hopkins reveal, in an elegant series of cell-line experiments, how the genetic disorder preferentially affects the corpus striatum, despite the fact that the mutant protein is found in cells throughout the body. Their findings are available in the journal Science.
But first some necessary background…
HD is characterized by the expansion of a 3-nucleotide repeat section in the gene that encodes for the protein huntingtin (Htt). Neurotoxicity in HD is related to the cellular solubility of the mutant form of Htt, or mHtt. Protein aggregates of mHtt appear to be neuroprotective, whereas soluble mHtt is associated with cytotoxicity. It is also important to note that the mutant protein is sumoylated—meaning that it is covalently bound to a small ubiquitin-like modifier (SUMO)—which reduces neuroprotective protein aggregation.
Investigating Rhes protein…
The Hopkins investigators chose to examine the relationship between mHtt and the protein Rhes, because the latter is very selectively expressed in the corpus striatum. By using striatal (mouse) cell lines that overexpressed Rhes or that were Rhes deficient, investigators determined that Rhes binds “robustly” to endogenous Htt—but much more so to mHtt than to wild-type Htt. Moreover, overexpression of Rhes, in particular, profoundly affected the survival of cells that expressed mHtt (but not those expressing wild-type Htt). Specifically they found that the cytotoxic effect of overexpressed Rhes was concentration dependent. And in a final set of experiments, investigators determined that overexpressed Rhes augments the sumoylation of mHtt, thereby causing the disaggregation of mHtt and cell death.
So…it appears that striatal Rhes promotes localized neuronal degeneration in HD by enhancing the sumoylation of mHtt. Drugs that block the interaction between Rhes and mHtt may have therapeutic potential in HD, the authors conclude.
Public-domain photo of American folk legend Woody Guthrie, who died of complications due to HD in 1967.