Perry disease (Perry syndrome) is a rare, rapidly progressive, autosomal dominant neurodegenerative disease characterized by parkinsonism, depression/apathy, weight loss, and respiratory symptoms ...including central hypoventilation. It is caused by missense mutations (e.g. p.G71A) in the DCTN1 gene. We previously generated transgenic mice that expressed human DCTN1
mutant protein under the control of Thy1 promoter. These mice exhibited apathy-like behavior and parkinsonism. However, it is possible that this phenotype was due to a gene-dosage imbalance or transgene insertion position. To circumvent these potential caveats, we have generated a knock-in mouse model carrying a p.G71A mutation in Dctn1. Heterozygous Dctn1
and wild-type littermates were subjected to a battery of behavioral analyses. Furthermore, immunohistochemistry for tyrosine hydroxylase (TH) was performed on brain sections of these mice, and TH signal intensity in substantia nigral neurons was quantified. Dctn1
mice were immobile for longer than wild-type mice of the same age and sex in the tail-suspension test, revealing depressive characteristics. In addition, the beam-walking test and pole test detected motor deficits in Dctn1
female mice. Finally, immunostaining revealed a decrease in TH immunoreactivity in neurons of the substantia nigra in the Dctn1
mice. Collectively, heterozygous Dctn1
mice showed depression-like behavior, motor deficits, and a functional reduction in substantia nigral neurons, as judged by TH immunostaining, thereby exhibiting multiple features of Perry disease. Hence, this mouse model will be useful in elucidating pathological mechanisms of Perry disease and for developing novel therapeutic strategies against it.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Perry syndrome is a rare neurodegenerative disease characterized by parkinsonism, depression/apathy, weight loss, and central hypoventilation. Our previously-conducted genome-wide association scan ...and subsequent studies identified nine mutations in DCTN1, the largest protein subunit of the dynactin complex, in patients with Perry syndrome. These included G71A in the microtubule-binding cytoskeleton-associated protein Gly-rich domain of p150
. The dynactin complex is essential for function of the microtubule-based cytoplasmic retrograde motor dynein. To test the hypothesis that the G71A mutation in the DCTN1 gene is sufficient to cause Perry syndrome, we generated DCTN1
transgenic mice. These mice initially developed normally, but young animals showed decreased exploratory activity and aged animals showed impaired motor coordination. These behavioral defects parallel apathy-like symptoms and parkinsonism encountered in Perry syndrome. TDP-43 aggregates were not detected in the substantia nigra and cerebral cortex of the transgenic mice, although pathological aggregates of TDP-43 have been considered a major neuropathological feature of Perry syndrome. Our study reveals that a single mutation in the DCTN1 gene recapitulates symptoms of Perry syndrome patients, and provides evidence that DCTN1
transgenic mice represent a novel rodent model of Perry syndrome.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
To establish science-based I -bar clasp design of removable partial denture (RPD), the dimension of I -bar clasps of RPD patients was measured, and the stiffness and stress distribution of these I ...-bar clasps were evaluated with the finite element method. The results were as follows 1. The thicknesses and widths incross-sections of I -bar clasps were 0.3-1.0. 2. The width of the taper of horizontal arms of I -bar clasps was the largest (0.09). 3. The stiffness of I -bar clasps was greater than that of mechanical ideal I -bar clasps. 4. The stress analysis suggests a possibility of fatigue fracture or permanent deformation of I -bar clasps. 5. It may be more preferable to fabricate I -bar clasp arms thinner than commonly used arms. An Ibar clasp with a taper of 0.02 in width is preferred.
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