TorsinA May Have Critical Role in Health of Basal Ganglia Neurons

Not long ago, a team of researchers led by DMRF Stanley Fahn Award Recipient William Dauer, MD, Associate Professor of Neurology at University of Michigan, published a remarkable study linking dystonia symptoms in mice to a loss of neurons in certain brain structures and abnormalities in a cellular protein called TorsinA. This is a departure from the widespread observation that isolated (primary) dystonia is not characterized by structural changes in the brain. In the continuation of this work, researchers have made further discoveries regarding the origins of dystonia in the nervous system.

Dystonia symptoms originate in part from problems in an area of the brain called the striatum (part of the basal ganglia). The striatum is made up of different types of neurons, but it remains unclear which of these are susceptible to degeneration in dystonia.

The investigators discovered that deleting the gene for TorsinA from certain neurons in mice (including in the striatum) causes abnormal twisting movements. The mice developed symptoms at a stage of brain development equivalent to the typical human age of onset. The movements were suppressed with anticholinergic medications, which are commonly used to treat human patients. The investigators analyzed brain tissue from the mice and found that the twisting movements began at the same time that a type of neuron in the striatum called cholinergic interneurons degenerated. Postmortem studies of dystonia patients have also revealed abnormalities in these neurons.

The neuron loss seen in the mice occurs only in specific brain structures involved in movement control and only for a period of time that coincides with the onset of symptoms. These findings challenge the notion that dystonia occurs in a structurally normal nervous system and suggest that cholinergic interneurons in the striatum require TorsinA to survive. The next challenge is to identify what causes the targeted loss of cholinergic interneurons and to investigate how this cell loss affects the striatum.