CNRS and Inserm research scientists at the Institut Curie have shed new light on the function of huntingtin, the protein whose mutation underlies Huntington’s disease. This neurodegenerative disease, like Alzheimer’s or Parkinson’s, is characterized by the abnormal death of certain neurons.
The scientists have discovered that huntingtin, like a "booster rocket", accelerates the transport of a neuron survival factor. When huntingtin is mutated, the “booster rocket” malfunctions, transport slows, protection wanes, and neurons die.
This discovery, published in the 9 July 2004 issue of Cell, could in time lead to novel therapeutic methods of blocking the accelerated death of neurons.
Huntington’s disease is a genetic disorder which affects some 6 000 people in France and concerns over 12 000 carriers of the mutated gene who for the time being are free of clinical signs. It is characterized by uncontrollable movements, personality changes, dementia and death 10 to 20 years after onset of the first symptoms (see box).
The gene responsible for this disease has been identified. It codes for the protein huntingtin, whose function until now has been poorly understood. One thing is sure, huntingtin protects neurons against cell death. But when it is mutated, the reverse happens: by a mechanism as yet unelucidated, the mutation in huntingtin leads to accelerated death of neurons in the striatum, the brain region where Huntington’s disease arises.
Huntingtin: a "booster rocket"
To understand how huntingtin controls neuronal survival, Laurent Gauthier and Bénédicte Charrin, directed by Sandrine Humbert(1) and Frédéric Saudou(2) at the Institut Curie, used 3D videomicroscopy (see image) to observe the effect of huntingtin.
In its normal state, huntingtin "boosts" the transport of BDNF(3), which is needed for survival of neurons in the striatum. BDNF "manufactured" in the cortex is thus transported to the striatum: ß along microtubules acting as "rails": these long specialized filaments are uniformly distributed in cells and transport molecules to their destinations;
ß by molecular motors acting as "locomotives": these motor proteins harness the energy of ATP to "run" along the microtubular “rails” in one direction with proteins in tow.