Genetic Modifiers of Penetrance in DYT1 Dystonia

Some types of dystonia are hereditary, for example, DYT1 dystonia caused by mutation in the TOR1A gene. It is not clear, however, why individuals with the same genetic mutation can develop different severities of symptoms. On the extremes, one individual may experience severe dystonia that starts in childhood and leads to significant motor disability while another individual may be totally asymptomatic and not even aware of having the genetic mutation. The researchers believe that other genes, yet to be discovered, determine wither an individual carrying a potentially dystonia-causing genetic mutation will develop this movement disorder or not. They propose to find this gene(s) by comparing the genomes of individuals who have mutation in the TOR1A gene, with or without apparent dystonia symptoms. The goal is to find genes that protect some individuals from developing dystonia, even in the presence of the mutated gene.

The Role of Cholinergic Neurons in Isolated Focal Cervical Dystonia

Cervical dystonia produces excessive involuntary muscle contractions in the neck. These muscle contractions result in uncomfortable, awkward, and sometimes painful positions of the head, neck, and shoulders. This research project focuses on improving understanding of the brain’s role in cervical dystonia, specifically directed toward improved treatment. The investigators will use state-of-the-art brain imaging techniques, positron emission tomography (PET) and magnetic resonance imaging (MRI), to observe the working brain. PET allows researchers to observe chemical messengers (neurotransmitters) in the brain, in this case acetylcholine. MRI allows researchers us to observe how one region of the brain communicates with other brain regions. Combining PET and MRI techniques provides a powerful opportunity to determine how altered chemical messenger levels may influence the way brain regions communicate in cervical dystonia by comparing brain activity of patients with cervical dystonia and control volunteers without cervical dystonia. Acetylcholine is a neurotransmitter of interest because some dystonia patients improve when taking medications that alter levels of acetylcholine. The researchers suspect that brain regions that use acetylcholine are damaged in patients with cervical dystonia and therefore the communication between brain regions that rely on acetylcholine is disrupted. If they find that acetylcholine affects how brain regions communicate in cervical dystonia, future research can attempt to correct the communication problem with new medication or brain stimulation therapies.

Cholinergic Interneuron Dysfunction in a Phenotypic Mouse Model of Dystonia

Dystonia is challenging to adequately treat, particularly because the underlying brain circuitry problem is not well understood. Studies indicate that a specific population of brain cells, namely striatal cholinergic interneurons, is dysfunctional in both dystonia animal models and in dystonia patients. Accordingly, dystonia is most effectively treated with drugs that reduce striatal cholinergic interneuron function, suggesting that enhanced cholinergic function may play a key role in dystonia. Utilizing a genetic animal model of dystonia that exhibits dystonia triggered by caffeine (transgenic paroxysmal nonkinesigenic dyskinesia (PNKD) mutant mice), the researchers have obtained preliminary data showing striatal cholinergic interneuron dysfunction similar to that observed in non-manifesting dystonia models. In this proposal, they will attempt to correlate dysfunction of striatal cholinergic interneurons with dystonic symptoms in dystonia-manifesting PNKD mice. They expect the experiments to answer crucial questions necessary for linking disease causing mutations to abnormal movements.