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Membrane Defects and Genetic Redundancy: Are We at a Turning Point for DYT1 Dystonia?

Journal Contribution - Journal Article

Heterozygosity for a 3-base pair deletion (DGAG) 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 dis- ease from research spanning structural biochemistry, cell science, neurobiology, and several model organisms. We now know that homozygosity for DGAG has the same effects as Tor1a KO, implicating a partial loss of function mechanism in the DGAG/1 disease state. In addition, tor- sinA loss specifically affects neurons in mice, even though the gene is broadly expressed, apparently because of dif- ferential 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 DGAG inhibits torsinA ATPase activity is defined, although mutant torsinA DGAG protein 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 advan- ces toward understanding the molecular, cellular, and neu- robiological pathologies of DYT1/TOR1A dystonia that can hopefully be exploited for new approaches to treat this disease.
Journal: MOVEMENT DISORDERS
ISSN: 0885-3185
Issue: 3
Volume: 32
Pages: 371 - 381
Publication year:2016
BOF-keylabel:yes
IOF-keylabel:yes
BOF-publication weight:6
CSS-citation score:1
Authors from:Higher Education
Accessibility:Closed