Phosphorylation of Munc18-1 by Dyrk1A regulates its interaction with Syntaxin 1 and X11α.

Dual-specificity tyrosine(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) is a protein kinase that might be responsible for mental retardation and early onset of Alzheimer's disease in Down's syndrome patients. Dyrk1A plays a role in many cellular pathways through phosphorylation of diverse substrate proteins; however, its role in synaptic vesicle exocytosis is poorly understood. Munc18-1, a central regulator of neurotransmitter release, interacts with Syntaxin 1 and X11α. Syntaxin 1 is a key soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein involved in synaptic vesicle docking/fusion events, and X11α modulates amyloid precursor protein processing and ß amyloid generation. In this study, we demonstrate that Dyrk1A interacts with and phosphorylates Munc18-1 at the Thr(479) residue. The phosphorylation of Munc18-1 at Thr(479) by Dyrk1A stimulated binding of Munc18-1 to Syntaxin 1 and X11α. Furthermore, the levels of phospho-Thr(479) -Munc18-1 were enhanced in the brains of transgenic mice over-expressing Dyrk1A protein, providing in vivo evidence of Munc18-1 phosphorylation by Dyrk1A. These results reveal a link between Munc18-1 and Dyrk1A in synaptic vesicle trafficking and amyloid precursor protein processing, suggesting that up-regulated Dyrk1A in Down's syndrome and Alzheimer's disease brains may contribute to some pathological features, including synaptic dysfunction and cognitive defect through abnormal phosphorylation of Munc18-1.

Radiocapitellar incongruity of the radial head in magnetic resonance imaging correlates with pathologic changes of the lateral elbow stabilizers in lateral epicondylitis.

OBJECTIVE: Post-traumatic posterolateral rotatory instability (PLRI) can be shown as radiocapitellar incongruity or posterior translation (PT) of the radial head in magnetic resonance imaging (MRI). We aimed to evaluate whether PT correlated with pathologic changes of lateral elbow stabilizers in patients with lateral epicondylitis. MATERIALS AND METHODS: In MRIs of 160 patients with lateral epicondylitis, we measured PT of the radial head in the sagittal images. We qualitatively graded five lesions of the lateral elbow structures that included common extensor tendon (CET) lesion (grade 1-3), lateral collateral ligament complex (LCLC) insufficiency (grade 0-2), and absence or presence of bone marrow signal change, osteochondral lesion, and calcification. We analyzed whether the PT correlated with pathologic changes of the lateral elbow stabilizers and evaluated the diagnostic value of the PT for severe lesions. RESULTS: The average PT was 1.9 mm. The PT correlated with both the CET lesion (p < 0.001) and LCLC insufficiency (p < 0.001). The optimal cutoff values of the PT for grade 3 CET lesion and grade 2 LCLC lesion were 2.6 and 2.8 mm, respectively. When potential PLRI was defined as the PT of > 3.4mm as suggested for post-traumatic PLRI, 21 patients had potential PLRI. The positive predictive values of the PT > 3.4mm were 76% for grade 3 CET lesions and 67% for grade 2 LCLC insufficiency. CONCLUSION: This study demonstrates that PT of the radial head correlates with pathological changes of the lateral elbow stabilizers. As radiocapitellar incongruity is easy to measure quantitatively, it can be used for screening potential PLRI in patients with lateral epicondylitis.

Negative feedback Inhibition of NFATc1 by DYRK1A regulates bone homeostasis.

DYRK1A is a serine/threonine kinase that has been linked to mental retardation associated with Down syndrome. In the present report, we describe a previously unknown role for DYRK1A in bone homeostasis. The protein expression of DYRK1A increased during osteoclast differentiation. In vitro studies in osteoclasts revealed that DYRK1A inhibited osteoclastogenesis. Whereas DYRK1A phosphorylated and inhibited the osteoclastogenic transcription factor NFATc1, forced expression of NFATc1 induced DYRK1A expression, suggesting a negative feedback loop. Transgenic mice overexpressing DYRK1A by the extent of the increased gene dosage in Down syndrome exhibited significantly reduced bone mass despite the decreased osteoclastogenesis, which is reminiscent of osteoporotic bone phenotype in Down syndrome patients. In these mice, attenuated osteoblast differentiation and function in the presence of extra DYRK1A overrode the effect of impaired osteoclastogenesis. However, impeded osteoclastogenesis in DYRK1A transgenic mice was proven to be beneficial in protecting bone loss induced by inflammation or estrogen deficiency. These results provide novel insight into the role for DYRK1A in bone homeostasis as well as in bone destructive diseases, in which modulation of DYRK1A might be used as a strategy to treat unregulated bone resorption.

Evaluation and Management of Osteoporosis and Sarcopenia in Patients with Distal Radius Fractures.

Distal radius fractures (DRFs) are one of the most common fractures seen in elderly people. Patients with DRFs have a high incidence of osteoporosis and an increased risk of subsequent fractures, subtle early physical performance changes, and a high prevalence of sarcopenia. Since DRFs typically occur earlier than vertebral or hip fractures, they reflect early changes of the bone and muscle frailty and provide physicians with an opportunity to prevent progression of frailty and secondary fractures. In this review, we will discuss the concept of DRFs as a medical condition that is at the start of the fragility fracture cascade, recent advances in the diagnosis of bone fragility including emerging importance of cortical porosity, fracture healing with osteoporosis medications, and recent progress in research on sarcopenia in patients with DRFs.

Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer's disease.

Most individuals with Down Syndrome (DS) show an early-onset of Alzheimer's disease (AD), which potentially results from the presence of an extra copy of a segment of chromosome 21. Located on chromosome 21 are the genes that encode beta-amyloid (Abeta) precursor protein (APP ), a key protein involved in the pathogenesis of AD, and dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A (DYRK1A ), a proline-directed protein kinase that plays a critical role in neurodevelopment. Here, we describe a potential mechanism for the regulation of AD pathology in DS brains by DYRK1A-mediated phosphorylation of APP. We show that APP is phosphorylated at Thr668 by DYRK1A in vitro and in mammalian cells. The amounts of phospho-APP and Abeta are increased in the brains of transgenic mice that over-express the human DYRK1A protein. Furthermore, we show that the amounts of phospho-APP as well as those of APP and DYRK1A are elevated in human DS brains. Taken together, these results reveal a potential regulatory link between APP and DYRK1A in DS brains, and suggest that the over-expression of DYRK1A in DS may play a role in accelerating AD pathogenesis through phosphorylation of APP.