A new Duke University study says that a protein critical for wiring the brain is mutated in early life among patients of Huntington’s disease, a progressive neurodegenerative disorder that leads to symptoms like uncontrolled movements, inability to focus or remember, depression and aggression. These symptoms appear usually in middle age by which time the disease has already ravaged the brain.
Published in the Journal of Neuroscience the new findings give further credence to the theory that traces Huntington’s and other neurodegenerative disorders like Alzheimer’s to childhood said lead author Cagla Eroglu. “These findings mean that if we understood the errors that develop during early life then we may be able to interfere with the first stage of the disease, before it shows itself. Before this the possibility of Huntington (Htt) protein playing a direct role in synapse formation was not explored.”
The scientists created mice in which Htt is deleted only in the cortex, a part of the brain implicated in the disease and controls perception, memory and thought, to understand the protein’s role as synapses form. The synapse in mutant mice formed more rapidly than in the healthy ones at three weeks of age, equivalent to first two years of human life, a time when a mouse begins to take in its surroundings through its eyes and ears.
However, by five weeks a time when in a process called pruning some synapses strengthen and others weaken the synapses in the mutant mice had completely deteriorated. The team also found severe alterations of the synaptic physiology including faulty circuits and signs of cellular stress in the brain in the very spot within the cortex that extends to the striatum, another brain area targeted by Huntington’s disease in people. Similar to human patients, the scientists observed that the mice have one normal copy of the Htt gene and one mutated copy, which produces a protein that is present in cells but in expanded form. In the model animals the synapses matured much faster than normal in the cortex and then died off.
The new results suggest that prolonged absence of Htt may affect the development but also the maintenance of healthy synapses. In the current strategy of treating Huntington’s disease that involves dialling down Htt levels in the brain using gene therapy or small-molecule inhibitors this finding is particularly relevant. However, it has been a challenge to target the mutated copy of the gene, not the normal copy.