title: Membrane defects and genetic redundancy: Are we at a turning point for DYT1 dystonia?
abstract: Heterozygosity for a 3-base pair deletion (ΔGAG) in TOR1A/torsinA is one of the most common causes of hereditary dystonia. In this review, we highlight current understanding of how this mutation causes disease from research spanning structural biochemistry, cell science, neurobiology, and several model organisms. We now know that homozygosity for ΔGAG has the same effects as Tor1aKO, implicating a partial loss of function mechanism in the ΔGAG/+ disease state. In addition, torsinA loss specifically affects neurons in mice, even though the gene is broadly expressed, apparently because of differential expression of homologous torsinB. Furthermore, certain neuronal subtypes are more severely affected by torsinA loss. Interestingly, these include striatal cholinergic interneurons that display abnormal responses to dopamine in several Tor1a animal models. There is also progress on understanding torsinA molecular cell biology. The structural basis of how ΔGAG inhibits torsinA ATPase activity is defined, although mutant torsinAΔGAGprotein also displays some characteristics suggesting it contributes to dystonia by a gain-of-function mechanism. Furthermore, a consistent relationship is emerging between torsin dysfunction and membrane biology, including an evolutionarily conserved regulation of lipid metabolism. Considered together, these findings provide major advances toward understanding the molecular, cellular, and neurobiological pathologies of DYT1/TOR1A dystonia that can hopefully be exploited for new approaches to treat this disease. © 2016 International Parkinson and Movement Disorder Society.
authors.affiliation: Vlaams Instituut voor Biotechnologie Centre for the Biology of Disease, Leuven, Belgium.|KU Leuven, Department of Human Genetics, Leuven, Belgium.
authors.forename: Ana
authors.initials: A
authors.lastname: Cascalho
authors.affiliation: Vlaams Instituut voor Biotechnologie Centre for the Biology of Disease, Leuven, Belgium.|KU Leuven, Department of Human Genetics, Leuven, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Jacquemyn
authors.affiliation: Vlaams Instituut voor Biotechnologie Centre for the Biology of Disease, Leuven, Belgium.|KU Leuven, Department of Human Genetics, Leuven, Belgium.
authors.forename: Rose E
authors.initials: RE
authors.lastname: Goodchild
mesh_terms: D000818:Animals; D004422:Dystonia Musculorum Deformans / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; C108175:TOR1A protein, human
keywords: dystonia; endoplasmic reticulum; membrane; nuclear envelope; torsinA