Chemical enhancement of torsinA function in cell and animal models of torsion dystonia

Songsong Cao, Jeffrey W. Hewett, Fumiaki Yokoi, Jun Lu, Amber Clark Buckley, Alexander J. Burdette, Pan Chen, Flavia C. Nery, Yuqing Li, Xandra O. Breakefield, Guy A. Caldwell, Kim A. Caldwell

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Movement disorders represent a significant societal burden for which therapeutic options are limited and focused on treating disease symptomality. Early-onset torsion dystonia (EOTD) is one such disorder characterized by sustained and involuntary muscle contractions that frequently cause repetitive movements or abnormal postures. Transmitted in an autosomal dominant manner with reduced penetrance, EOTD is caused in most cases by the deletion of a glutamic acid (ΔE) in the DYT1 (also known as TOR1A) gene product, torsinA. Although some patients respond well to anticholingerics, therapy is primarily limited to either neurosurgery or chemodenervation. As mutant torsinA (ΔE) expression results in decreased torsinA function, therapeutic strategies directed toward enhancement of wild-type (WT) torsinA activity in patients who are heterozygous for mutant DYT1 may restore normal cellular functionality. Here, we report results from the first-ever screen for candidate small molecule therapeutics for EOTD, using multiple activity-based readouts for torsinA function in Caenorhabditis elegans, subsequent validation in human DYT1 patient fibroblasts, and behavioral rescue in a mouse model of DYT1 dystonia. We exploited the nematode to rapidly discern chemical effectors of torsinA and identified two classes of antibiotics, quinolones and aminopenicillins, which enhance WT torsinA activity in two separate in vivo assays. Representative molecules were assayed in EOTD patient fibroblasts for improvements in torsinA-dependent secretory function, which was improved significantly by ampicillin. Furthermore, a behavioral defect associated with an EOTD mouse knock-in model was also rescued following administration of ampicillin. These combined data indicate that specific small molecules that enhance torsinA activity represent a promising new approach toward therapeutic development for EOTD, and potentially for other diseases involving the processing of mutant proteins.

Original languageEnglish (US)
Pages (from-to)386-396
Number of pages11
JournalDMM Disease Models and Mechanisms
Volume3
Issue number5-6
DOIs
StatePublished - May 2010
Externally publishedYes

Fingerprint

Dystonia Musculorum Deformans
Torsional stress
Animals
Animal Models
Fibroblasts
Ampicillin
Molecules
Neurosurgery
Therapeutics
Penetrance
Dystonia
Nerve Block
Quinolones
Dyskinesias
Caenorhabditis elegans
Movement Disorders
Mutant Proteins
Muscle Contraction
Posture
Smooth Muscle

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Neuroscience (miscellaneous)

Cite this

Cao, S., Hewett, J. W., Yokoi, F., Lu, J., Buckley, A. C., Burdette, A. J., ... Caldwell, K. A. (2010). Chemical enhancement of torsinA function in cell and animal models of torsion dystonia. DMM Disease Models and Mechanisms, 3(5-6), 386-396. https://doi.org/10.1242/dmm.003715

Chemical enhancement of torsinA function in cell and animal models of torsion dystonia. / Cao, Songsong; Hewett, Jeffrey W.; Yokoi, Fumiaki; Lu, Jun; Buckley, Amber Clark; Burdette, Alexander J.; Chen, Pan; Nery, Flavia C.; Li, Yuqing; Breakefield, Xandra O.; Caldwell, Guy A.; Caldwell, Kim A.

In: DMM Disease Models and Mechanisms, Vol. 3, No. 5-6, 05.2010, p. 386-396.

Research output: Contribution to journalArticle

Cao, S, Hewett, JW, Yokoi, F, Lu, J, Buckley, AC, Burdette, AJ, Chen, P, Nery, FC, Li, Y, Breakefield, XO, Caldwell, GA & Caldwell, KA 2010, 'Chemical enhancement of torsinA function in cell and animal models of torsion dystonia', DMM Disease Models and Mechanisms, vol. 3, no. 5-6, pp. 386-396. https://doi.org/10.1242/dmm.003715
Cao, Songsong ; Hewett, Jeffrey W. ; Yokoi, Fumiaki ; Lu, Jun ; Buckley, Amber Clark ; Burdette, Alexander J. ; Chen, Pan ; Nery, Flavia C. ; Li, Yuqing ; Breakefield, Xandra O. ; Caldwell, Guy A. ; Caldwell, Kim A. / Chemical enhancement of torsinA function in cell and animal models of torsion dystonia. In: DMM Disease Models and Mechanisms. 2010 ; Vol. 3, No. 5-6. pp. 386-396.
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