Early onset generalized dystonia is a common but poorly understood movement disorder, affecting young people, with little meaningful intervention. Clinical evidence has strongly implicated abnormal dopaminergic transmission in the basal ganglia as a major etiology of dystonia. Two recent findings by our colleagues now allow the investigation of the molecular and cellular basis of early onset dystonia: 1) a strong candidate gene DYTl has been identified on human chromosome 9, and 2) expression of the DYTl message in the brain is restricted neuroanatomically to the substantia nigra, cerebellum and hippocampus. The DYTl gene product, torsinA, is a member of a novel family of human genes (torsin-related proteins) of unknown function. TorsinA has sequence homology with functional domains of the large Clp ATPase/HSP100 gene family. Prototype members of this family are characterized by ATP-binding and formation of functional oligomeric complexes. This project is designed to use an efficient expression system to test hypothesis of torsinA function modeled from its homology to the Clp/Hsp family, including protein stability in stress conditions. The regulation of torsinA gene expression, subcellular distribution of the protein will be determined in neuronal cell lines and primary neuron cultures. The role of mutant torsinA as a dominant negative will be measured directly in functional studies of neuronal function, such as stress response, oxidative phosphorylation and dopamine release. The expression system will be designed to differentiate different torsin members, and mutant from wild type torsinA and allow efficient delivery into neurons in different experimental systems. This expression system is designed as a 'bridge' technology, to link the new discoveries of the genetics of the torsins to the cell biology and function of these proteins in the normal and diseased state.
| Waugh, Jeff L; Kuster, John K; Levenstein, Jacob M et al. (2016) Thalamic Volume Is Reduced in Cervical and Laryngeal Dystonias. PLoS One 11:e0155302 |
| Sundermann, Erin Elizabeth; Wang, Cuiling; Katz, Mindy et al. (2016) Cholesteryl ester transfer protein genotype modifies the effect of apolipoprotein ?4 on memory decline in older adults. Neurobiol Aging 41:200.e7-200.e12 |
| DeAndrade, Mark P; Trongnetrpunya, Amy; Yokoi, Fumiaki et al. (2016) Electromyographic evidence in support of a knock-in mouse model of DYT1 Dystonia. Mov Disord 31:1633-1639 |
| de Carvalho Aguiar, Patricia; Borges, Vanderci; Ferraz, Henrique Ballalai et al. (2015) Novel compound heterozygous mutations in PRKRA cause pure dystonia. Mov Disord 30:877-8 |
| Alcalay, Roy N; Mejia-Santana, Helen; Mirelman, Anat et al. (2015) Neuropsychological performance in LRRK2 G2019S carriers with Parkinson's disease. Parkinsonism Relat Disord 21:106-10 |
| Saunders-Pullman, Rachel; Alcalay, Roy N; Mirelman, Anat et al. (2015) REM sleep behavior disorder, as assessed by questionnaire, in G2019S LRRK2 mutation PD and carriers. Mov Disord 30:1834-9 |
| Gupte, Manisha; Alcalay, Roy N; Mejia-Santana, Helen et al. (2015) Interest in genetic testing in Ashkenazi Jewish Parkinson's disease patients and their unaffected relatives. J Genet Couns 24:238-46 |
| Mirelman, Anat; Alcalay, Roy N; Saunders-Pullman, Rachel et al. (2015) Nonmotor symptoms in healthy Ashkenazi Jewish carriers of the G2019S mutation in the LRRK2 gene. Mov Disord 30:981-6 |
| Yokoi, Fumiaki; Dang, Mai T; Liu, Jun et al. (2015) Decreased dopamine receptor 1 activity and impaired motor-skill transfer in Dyt1 ?GAG heterozygous knock-in mice. Behav Brain Res 279:202-10 |
| Yokoi, Fumiaki; Chen, Huan-Xin; Dang, Mai Tu et al. (2015) Behavioral and electrophysiological characterization of Dyt1 heterozygous knockout mice. PLoS One 10:e0120916 |
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