30 June 2000. The discovery that Huntington's disease results from a particular
mutation of the gene for the protein dubbed "huntingtin" has created great hope
that this neurodegenerative movement disorder will soon have effective treatments.
Because huntingtin forms aggregates in a manner similar to amyloid-β, advances
in HD research are also of particular interest to Alzheimer's researchers. In
a paper published in the journal Cell, a group of researchers at Columbia University
have recently demonstrated that when production of the abnormal protein is turned
off, the aggregates disappear and many disease hallmarks are halted or even reversed.
The researchers made use of a particularly interesting gene system that is
tetracycline-sensitive. It is, in essence, an on/off switch that can be transfected
into laboratory mice and then used to turn genes off simply by adding a tetracycline
analog to an animal's diet. They fused the tetracycline-sensitive genes to a
gene that codes for the disease-causing huntingtin mutation. The resulting animals
have huntingtin genes that are always on-constantly producing the abnormal
huntingtin protein, which forms nuclear aggregates in the same pattern as in
the human disease. More importantly, these mice developed the motor disturbances
characteristic of Huntington's.
A subgroup of mice were fed tetracycline from the age of four months (an age
at which Huntington's neuropathology and behavioral deficits are already detectable),
with the effect of turning off transcription of the gene complex that includes
the mutant huntingtin gene. In these animals, the aggregates of huntingtin disappeared
and the motor deficits were ameliorated. Other benefits included the halting
of striatal atrophy and dopamine D1 receptor loss. The important message of
this result for research into other neurodegenerative diseases involving abnormal
protein aggregations is that in Huntington's, constant expression of the mutant
gene is necessary for a progression of the disease process. Furthermore, halting
this expression can halt or even reverse the disease.-Hakon Heimer.
Reference:Yamamoto A, Lucas JJ, Hen R. Cell 2000;101:57-66. Abstract