Phosphorylation by Dyrk1A of Clathrin Coated Vesicle-Associated Proteins: Identification of the Substrate Proteins and the Effects of Phosphorylation

Dyrk1A phosphorylated multiple proteins in the clathrin-coated vesicle (CCV) preparations obtained from rat brains. Mass spectrometric analysis identified MAP1A, MAP2, AP180, and α- and β-adaptins as the phosphorylated proteins in the CCVs. Each protein was subsequently confirmed by [32P]-labeling and immunological methods. The Dyrk1A-mediated phosphorylation released the majority of MAP1A and MAP2 and enhanced the release of AP180 and adaptin subunits from the CCVs. Furthermore, Dyrk1A displaced adaptor proteins physically from CCVs in a kinase-concentration dependent manner. The clathrin heavy chain release rate, in contrast, was not affected by Dyrk1A. Surprisingly, the Dyrk1A-mediated phosphorylation of α- and β-adaptins led to dissociation of the AP2 complex, and released only β-adaptin from the CCVs. AP180 was phosphorylated by Dyrk1A also in the membrane-free fractions, but α- and β-adaptins were not. Dyrk1A was detected in the isolated CCVs and was co-localized with clathrin in neurons from mouse brain sections and from primary cultured rat hippocampus. Previously, we proposed that Dyrk1A inhibits the onset of clathrin-mediated endocytosis in neurons by phosphorylating dynamin 1, amphiphysin 1, and synaptojanin 1. Current results suggest that besides the inhibition, Dyrk1A promotes the uncoating process of endocytosed CCVs

Perceived Barriers and Facilitators for an Academic Career in Geriatrics: Medical Students’ Perspectives

ObjectiveThere is a growing concern about a shortage of physician scientists. This problem is particularly severe in certain subspecialties such as geriatrics in general and geriatric psychiatry in particular. This study sought to obtain medical students' perspectives on barriers and facilitators toward pursuing a career in academics and/or in geriatric psychiatry or geriatic medicine.MethodsThe study surveyed 27 first-year medical students from six US medical schools, who had demonstrated a clear interest in academic geriatrics by completing a mentored summer research training program in geriatric medicine or geriatric psychiatry, funded by the National Institute on Aging. The survey included open-ended and close-ended questions about likely career choice and factors affecting it.ResultsSixty percent of students reported they were likely to pursue an academic career, 44 % a career in geriatric psychiatry or geriatic medicine, and only 36 % a career in academic geriatrics. The most frequently perceived barriers were a lack of knowledge about academic careers and lack of exposure to geriatrics, financial concerns due to loan debts and low compensation, and negative impressions of research and of working with older adults. Facilitators included positive experiences with or positive impressions of research and research mentors and of older adults, and the growing demand for geriatric care.ConclusionsAttracting capable and motivated medical students to academic careers in fields such as geriatric psychiatry or geriatic medicine should be a priority in seeking to expand the number of physician scientists and to add to the health-care workforce in underserved subspecialty areas. Necessary approaches should include opportunities to work in academic settings; availability of sustained and dedicated mentorship; early, consistent, and positive exposure to older adults; and financial incentives