Lack of a preclinical model of primary dystonia that exhibits dystonic-like twisting movements has stymied identification of the cellular and molecular underpinnings of the disease. The classical familial form of primary dystonia is caused by the DYT1 (ΔE) mutation in TOR1A, which encodes torsinA, AAA + ATPase resident in the lumen of the endoplasmic reticular/nuclear envelope. Here, we found that conditional deletion of Tor1a in the CNS (nestin-Cre Tor1a flox/-) or isolated CNS expression of DYT1 mutant torsinA (nestin-Cre Tor1a flox/ΔE ) causes striking abnormal twisting movements. These animals developed perinuclear accumulation of ubiquitin and the E3 ubiquitin ligase HRD1 in discrete sensorimotor regions, followed by neurodegeneration that was substantially milder in nestin-Cre Tor1a flox/ΔE compared with nestin-Cre Tor1a flox/-animals. Similar to the neurodevelopmental onset of DYT1 dystonia in humans, the behavioral and histopathological abnormalities emerged and became fixed during CNS maturation in the murine models. Our results establish a genetic model of primary dystonia that is overtly symptomatic, and link torsinA hypofunction to neurodegeneration and abnormal twisting movements. These findings provide a cellular and molecular framework for how impaired torsinA function selectively disrupts neural circuits and raise the possibility that discrete foci of neurodegeneration may contribute to the pathogenesis of DYT1 dystonia. IntroductionThe primary dystonias, a group of sporadic and inherited illnesses, are a striking example of selective vulnerability of CNS sensorimotor circuits (1, 2). Dystonia -defined as prolonged, involuntary twisting movements -is traditionally classified as "primary" if it occurs in isolation and in the absence of neuropathological change. In contrast, "secondary" dystonic movements occur consequent to CNS damage (e.g., from stroke, trauma, or neurodegeneration), and are typically accompanied by additional neurological signs and symptoms. This classification scheme has been criticized (3), however, because neuroimaging of patients with primary dystonia indicates the presence of subtle neuropathological changes, and few primary dystonia brains have been comprehensively analyzed (4). Indeed, despite considerable interest in the pathophysiology of primary dystonia, the molecular and cellular underpinnings of CNS dysfunction and the identity of affected motor structures and cell types remain poorly understood. DYT1 dystonia is a common inherited form of primary dystonia that typically manifests during a discrete period of childhood, implicating abnormal development as the cause of motor dysfunction. This neurodevelopmental disease is caused by a 3 bp in-frame mutation in TOR1A that removes a single glutamic acid residue (ΔE) from the torsinA protein. TorsinA is a ubiquitously expressed AAA + protein residing in the lumen of the ER/nuclear envelope (ER/NE) space (5-7). Accumulating evidence indicates that the DYT1 mutation acts by impairing torsinA function through multiple mechan...

Structural information provided by computed tomography (CT) can be used for quality control and optimization of processes for manufacturing better materials. The squeeze casting method for producing metal matrix composites involves infiltrating a preform of ceramic fibers with molten metal under high pressure. Part quality can be improved if CT is used before infiltration to determine if the preforms have the desired distribution of fibers and are free of defects. Measurements do not require uniform shapes, and CT systems can even be used to obtain accurate densities on complicated part shapes that are not amenable to bulk density measurements based on weight and size. With this quantitative distribution information as a guide, preform production can be modified to produce either a more uniform fiber distribution or to selectively increase the fiber concentration in critical areas. Problems occurring during later stages of processing can be detected in CT images of the completed part. For example. CT can be used to detect unreinforced regions in metal matrix composites caused by cracking of the preform during the squeeze casting process. CT scans of completed parts can also detect and distinguish variations in structure such as microporosity.

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