[Abstract Title]. - Society for Neuroscience

Program#/Poster#: 248.3/U2
Topic: C.03.j. Dystonia
Support: Bachmann-Strauss Dystonia Foundation
Title: Molecular cloning and characterization of zebrafish Torsin 1
Authors: *J. J. SAGER 1,2 , G. E. TORRES 1,3 , E. A. BURTON 4,5,2,6,7 ;
1 Neurobio., 2 Pittsburgh Inst. of Neurodegenerative Dis., 3 Pharmacol., 4 Neurol., 5 Mol. Genet. and
Biochem., Univ. Pittsburgh, Pittsburgh, PA; 6 Div. of Movement Disorders, Univ. of Pittsburgh
Med. Ctr., Pittsburgh, PA; 7 Pittsburgh VA Healthcare Syst., Pittsburgh, PA
Abstract: Early Onset Torsion Dystonia (EOTD) is a movement disorder caused by a mutation
in the dyt1 gene encoding TorsinA, an ATPase of the AAA+ superfamily. The disorder is
inherited as an autosomal dominant Mendelian trait with 30-40% penetrance. Patients with
EOTD have an in frame trinucletide deletion, resulting in the loss of a single glutamic acid near
the carboxyl terminal of Torsin A. It is believed that the mutant protein exerts a dominant
negative function, perhaps by effecting relocalization of wild-type protein to the nuclear
envelope from its usual position in the endoplasmic reticulum. The cellular functions of TorsinA
are unknown; the neuronal mechanisms that are perturbed by expression of mutant Torsin A are
a major unresolved issue in understanding the pathophysiology of dystonia. We aim to use the
genetically manipulable zebrafish as a model vertebrate central nervous system in which to
elucidate the functions and pathophysiology of TorsinA in vivo. As a first step towards this goal,
we have identified and cloned the zebrafish tor1 gene encoding the ortholog of human torsin 1A.
The tor1 gene shows alternative 5‟ exons that splice into a common transcript at exon 2; both
splice variants are expressed in zebrafish brain. Sequence analysis shows that the zebrafish and
human proteins share approximately 60% identity and almost 80% similarity, with complete
conservation of the catalytic domains, suggesting conserved biochemical functions and implying
that the zebrafish system will be informative for understanding the molecular physiology of
human torsin. Current studies are focused on delineating the expression pattern of zebrafish
Torsin1 and the effects of under or over expression in larval zebrafish.
Disclosures: J.J. Sager , None; G.E. Torres, None; E.A. Burton, None.
Poster
248. Dystonia
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 248.4/U3