The DYT1 carrier state increases energy demand in the olivocerebellar network.
DYT1 dystonia is caused by a GAG deletion in TOR1A, the gene which encodes torsinA. Gene expression studies in rodents and functional imaging studies in humans suggest that DYT1 dystonia may be a network disorder of neurodevelopmental origin. To generate high resolution metabolic maps of DYT1 dystonia and pinpoint dysregulated network elements, we performed 2-deoxyglucose autoradiography and cytochrome oxidase (CO) histochemistry in transgenic mice expressing human mutant (hMT1) torsinA and wild-type littermates. In comparison with controls, hMT1 mice showed increased glucose utilization (GU) in the inferior olive (IO) medial nucleus (IOM), IO dorsal accessory nucleus and substantia nigra compacta, and decreased GU in the medial globus pallidus (MGP) and lateral globus pallidus. The hMT1 mice showed increased CO activity in the IOM and Purkinje cell layer of cerebellar cortex, and decreased CO activity in the caudal caudate-putamen, substantia nigra reticulata and MGP. These findings suggest that (1) the DYT1 carrier state increases energy demand in the olivocerebellar network and (2) the IO may be a pivotal node for abnormal basal ganglia-cerebellar interactions in dystonia.
Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Y
Y
Zhao
N
N
Sharma
M S
MS
LeDoux
D000818:Animals; D002353:Carrier State / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism*; D004422:Dystonia Musculorum Deformans / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009415:Nerve Net / Q000378:metabolism*; D009434:Neural Pathways / Q000378:metabolism; D009847:Olivary Nucleus / Q000378:metabolism*
D018832:Molecular Chaperones; C108175:TOR1A protein, human
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