title: Untethering the nuclear envelope and cytoskeleton: biologically distinct dystonias arising from a common cellular dysfunction.
abstract: Most cases of early onset DYT1 dystonia in humans are caused by a GAG deletion in the TOR1A gene leading to loss of a glutamic acid (ΔE) in the torsinA protein, which underlies a movement disorder associated with neuronal dysfunction without apparent neurodegeneration. Mutation/deletion of the gene (Dst) encoding dystonin in mice results in a dystonic movement disorder termed dystonia musculorum, which resembles aspects of dystonia in humans. While torsinA and dystonin proteins do not share modular domain architecture, they participate in a similar function by modulating a structural link between the nuclear envelope and the cytoskeleton in neuronal cells. We suggest that through a shared interaction with the nuclear envelope protein nesprin-3α, torsinA and the neuronal dystonin-a2 isoform comprise a bridge complex between the outer nuclear membrane and the cytoskeleton, which is critical for some aspects of neuronal development and function. Elucidation of the overlapping roles of torsinA and dystonin-a2 in nuclear/endoplasmic reticulum dynamics should provide insights into the cellular mechanisms underlying the dystonic phenotype.
authors.affiliation: Neuroscience Center, Department of Neurology, Massachusetts General Hospital, East, Boston, MA 02114, USA.
authors.forename: Nadia A
authors.initials: NA
authors.lastname: Atai
authors.forename: Scott D
authors.initials: SD
authors.lastname: Ryan
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
authors.forename: Xandra O
authors.initials: XO
authors.lastname: Breakefield
authors.forename: Flávia C
authors.initials: FC
authors.lastname: Nery