Huntington’s disease is marked by uncoordinated gestures and disorganized movements, but the precise links between the genetic mutation in the huntingtin protein, affected neural circuits, and movement deficits remain unclear.
The neural circuitry underlying song production in zebra finches resembles circuits implicated in Huntington’s disease. Hence, researchers engineered adult male zebra finches to selectively produce a mutant huntingtin fragment in the songbirds’ so-called area X neurons, which correspond to the human basal ganglia—brain structures implicated in the disease.
Compared with normal finches, engineered birds vocalized a greater amount daily and sang songs with disorganized syllable sequences 1–2 months after intervention; the effect persisted for several months.
Changes in song were accompanied by loss of area X medium spiny neurons, reduced number of inhibitory synapses on pallidal neurons, and altered activity of lateral magnocellular nucleus of the anterior nidopallium (LMAN) neurons, the human counterparts of all of which are tied to the disease.
Reversible chemical blockade of LMAN neurons restored normal singing patterns in engineered birds. According to the authors, mutant huntingtin might trigger movement defects through its effects on temporal patterns of activity in the circuit involving the brain’s cortex and basal ganglia.
In a related article, another group of researchers explored the elusive function of huntingtin in adult tissues, in light of ongoing therapeutic attempts to hobble mutant huntingtin using genetic techniques in the adult mouse brain.
The authors report that depleting huntingtin in adult mouse neurons did not trigger Huntington’s disease-related neurodegeneration or discernible symptoms.
However, loss of huntingtin in 2-month-old mice proved lethal, likely due to acute pancreatitis, marked by the loss of pancreatic acinar cells, which undergo degeneration mediated by the digestive enzyme trypsin, normally kept in check by huntingtin.
Engineering a truncated huntingtin protein into huntingtin-depleted mice ameliorated pancreatitis and prevented death. According to the authors, huntingtin might thus play age- and cell type-specific roles in humans, and the findings together point to potential time-sensitive therapeutic targets for the disease.
http://www.pnas.org/content/early/2016/03/02/1523754113
Molecular insights into Huntington's disease
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