Wolfgang Hampe

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid β peptide (Aβ) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Aβ-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

SorLA Signaling by Regulated Intramembrane Proteolysis

The single-transmembrane receptor SorLA/LR11 contains binding domains typical for lipoprotein receptors and a VPS10 domain, which binds the neuropeptide head-activator. This undecapeptide enhances proliferation of neuronal precursor cells in a SorLA-dependent manner. Using specific inhibitors we found previously that head activator activates shedding of SorLA by the metalloprotease TACE close to the transmembrane domain releasing the large extra-cellular part of the receptor. Here we show that the remaining COOH-terminal membrane fragment of SorLA is processed by γ-secretase. Inhibition of γ-secretase by specific inhibitors or overexpression of dominant negative presenilin mutants and knock out of the presenilin genes led to accumulation of the SorLA membrane fragment and also of full-length SorLA in the membrane. In an in vitro assay we observed the γ-secretase-dependent release of the two soluble cleavage products, the SorLA cytoplasmic domain and the SorLA β-peptide. These processing steps are reminiscent of a novel signaling pathway that has been described for the notch receptor. Here, the notch cytoplasmic domain is released into the cytoplasm by the γ-secretase and migrates to the nucleus where it acts as a transcriptional regulator. In parallel we found that a fusion protein of the released cytoplasmic tail of SorLA with EGFP located to the nucleus only if the nuclear localization signal of SorLA was intact. In a reporter gene assay the cytoplasmic domain of SorLA acted as a transcriptional activator indicating that SorLA might directly regulate transcription after activation by γ-secretase.

Unique expression pattern of a novel mosaic receptor in the developing cerebral cortex

Recently, a new type of transmembrane protein with a unique combination of protein domains was characterized from human, rabbit and chicken. This protein exhibits features of the low-density lipoprotein receptor family and shows homology to the receptor of the neuropeptide head activator isolated from hydra. To study the temporal and spatial pattern of expression of this unusual new receptor we have isolated a murine homolog and, in accordance with its human counterpart, named it mSorLA. Northern blot analysis revealed the highest abundance of mSorLA transcripts in the adult brain, lower levels in a variety of other organs and expression during embryogenesis. In situ hybridization showed predominant localization in neurons of the cortex, the hippocampus and the cerebellum. During embryonic development mSorLA displayed a unique pattern of expression in the cerebral cortex, where a subpopulation of neurons was labeled before final differentiation. Transcripts of mSorLA were also detected outside the central nervous system in regions active in morphogenesis.

Identification of SorCS2, a novel member of the VPS10 domain containing receptor family, prominently expressed in the developing mouse brain.

We report the identification of a fourth member of the VPS10 domain containing receptor family, SorCS2, highly expressed in the developing and mature murine central nervous system. During early central nervous system development its main site of expression is the floor plate. In addition, high transcript levels were detected transiently in a variety of brain regions including the dopaminergic midbrain nuclei and the dorsal thalamus. Outside the nervous system expression is detected in lung and heart and transiently in a variety of mesodermally derived tissues.

Alternative splicing in the regulatory region of the human phosphatases CDC25A and CDC25C.

CDC25 phosphatases play key roles in cell proliferation by activating cell cycle-specific cyclin-dependent kinases (CDKs). We identified four new splice variants in the amino-terminal regulatory region of human cdc25C and one in cdc25A. All variants except one retain an intact catalytic domain. Alternative splicing results in loss of phosphorylation sites for kinases like CDK and the calcium/calmodulin-dependent kinase II (CaMKII), which influence CDC25 activity and compartmental localization. In NT2 teratocarcinoma cells, induced for nerve cell differentiation, the smaller sized variant of cdc25C was upregulated. At the protein level both phosphorylation state and isoform distribution differed between cell lines and cell cycle phases.

Hu-K4 is a ubiquitously expressed type 2 transmembrane protein associated with the endoplasmic reticulum

Hu‐K4 is a human protein homologous to the K4L protein of vaccinia virus. Due to the presence of two HKD motifs, Hu‐K4 was assigned to the family of Phospholipase D proteins although so far no catalytic activity has been shown. The Hu‐K4 mRNA is found in many human organs with highest expression levels in the central nervous system. We extended the ORF of Hu‐K4 to the 5′ direction. As a consequence the protein is 53 amino acids larger than originally predicted, now harbouring a putative transmembrane domain. The exon/intron structure of the Hu‐K4 gene reveals extensive alternative splicing in the 5′ untranslated region. Due to the absence of G/C‐rich regions and upstream ATG codons, the mRNA isoform in brain may be translated with higher efficacy leading to a high Hu‐K4 protein concentration in this tissue. Using a specific antiserum produced against Hu‐K4 we found that Hu‐K4 is a membrane‐bound protein colocalizing with protein disulfide isomerase, a marker of the endoplasmic reticulum. Glycosylation of Hu‐K4 as shown by treatment with peptide N‐glycosidase F or tunicamycin indicates that Hu‐K4 has a type 2 transmembrane topology.

Dimensionality and predictive validity of the HAM-Nat, a test of natural sciences for medical school admission

BackgroundKnowledge in natural sciences generally predicts study performance in the first two years of the medical curriculum. In order to reduce delay and dropout in the preclinical years, Hamburg Medical School decided to develop a natural science test (HAM-Nat) for student selection. In the present study, two different approaches to scale construction are presented: a unidimensional scale and a scale composed of three subject specific dimensions. Their psychometric properties and relations to academic success are compared.Methods334 first year medical students of the 2006 cohort responded to 52 multiple choice items from biology, physics, and chemistry. For the construction of scales we generated two random subsamples, one for development and one for validation. In the development sample, unidimensional item sets were extracted from the item pool by means of weighted least squares (WLS) factor analysis, and subsequently fitted to the Rasch model. In the validation sample, the scales were subjected to confirmatory factor analysis and, again, Rasch modelling. The outcome measure was academic success after two years.ResultsAlthough the correlational structure within the item set is weak, a unidimensional scale could be fitted to the Rasch model. However, psychometric properties of this scale deteriorated in the validation sample. A model with three highly correlated subject specific factors performed better. All summary scales predicted academic success with an odds ratio of about 2.0. Prediction was independent of high school grades and there was a slight tendency for prediction to be better in females than in males.ConclusionsA model separating biology, physics, and chemistry into different Rasch scales seems to be more suitable for item bank development than a unidimensional model, even when these scales are highly correlated and enter into a global score. When such a combination scale is used to select the upper quartile of applicants, the proportion of successful completion of the curriculum after two years is expected to rise substantially.

Function of the Neuropeptide Head Activator for Early Neural and Neuroendocrine Development

Head activator (HA) is an undecapeptide (Fig. 1) identical in sequence from hydra to mammals (Bodenmuller and Schaller 1981; Schaller and Bodenmuller 1981). In hydra HA occurs as a gradient with maximal concentration in the head region. As a morphogen HA is required for head-specific growth and differentiation processes, hence its name (reviewed in Schaller 1996; Schaller et al. 1996). In mammals HA is a growth factor for early nerve and neuroendocrine development, and it has modulatory functions later in life (Kajiwara and Sato 1986; Schaller et al. 1989; Quach et al. 1992; Ulrich et al. 1996; Kayser et al. 1998).

Wer wird ein guter Arzt

ZusammenfassungSeit 2005 können die deutschen Universitäten etwa 60% ihrer Medizin- und Zahnmedizinstudienplätze nach selbst gewählten Verfahren vergeben. 2008 ergaben die Auswahlverfahren ein buntes Bild: Einige Universitäten verwendeten ausschließlich die Abiturnote, andere zogen zusätzlich in unterschiedlicher Kombination Auswahlgespräche, Testverfahren, absolvierte Berufsausbildung oder Belege für wissenschaftliches, kulturelles oder soziales Engagement hinzu. Lediglich für die Abiturnote und einige Studierfähigkeitstests zeigen viele Studien eine akzeptable prognostische Validität zumindest in Bezug auf den Studienerfolg. Die Validität von Auswahlgesprächen oder anderen Merkmalen zur Messung nichtkognitiver Merkmale konnte nicht hinreichend belegt werden. In aktuellen Studien an den Medizinischen Fakultäten Hamburg und Heidelberg werden Prädiktoren wie ein Naturwissenschaftstest, die Abiturnote oder eine abgeschlossene Berufsausbildung beziehungsweise ein freiwilliges soziales Jahr auf ihre prognostische Validität untersucht. Wir empfehlen, in Auswahlverfahren neben der Abiturnote auch die Ergebnisse studienfachspezifischer schriftlicher, in der Zahnmedizin auch praktischer Tests, zu verwenden. Auswahlgespräche könnten sinnvoll sein, um Studienbewerbern die Wichtigkeit nichtkognitiver Eigenschaften zu vermitteln und sie stärker an die Fakultät zu binden.AbstractSince 2005, German universities are free to select 60% of their freshmen according to their own admission processes. In 2008, selection of medical students in Germany was mainly based on grades achieved in final school examinations (Abiturnote). Further criteria were used in various combinations: some medical schools conducted interviews or tests, while others rewarded work experience, research awards, or cultural and social dedication. However, solely high school grades and some measures of ability show acceptable validity coefficients with regard to academic and professional success. Evidence for the prognostic validity of interviews and other noncognitive criteria cannot be regarded as sufficient. Recent studies conducted in Hamburg and Heidelberg attempt to validate selection criteria such as a test of natural sciences, final school examination grades, work experience, and voluntary work in the social sector. For the selection of medical students, we recommend the use of final school examination grades in combination with special written test results or, in the case of dentistry, a test of manual dexterity. Interviews might be beneficial to emphasize the importance of non-academic skills and to strengthen the ties of students to their faculty.Since 2005, German universities are free to select 60% of their freshmen according to their own admission processes. In 2008, selection of medical students in Germany was mainly based on grades achieved in final school examinations (Abiturnote). Further criteria were used in various combinations: some medical schools conducted interviews or tests, while others rewarded work experience, research awards, or cultural and social dedication. However, solely high school grades and some measures of ability show acceptable validity coefficients with regard to academic and professional success. Evidence for the prognostic validity of interviews and other noncognitive criteria cannot be regarded as sufficient. Recent studies conducted in Hamburg and Heidelberg attempt to validate selection criteria such as a test of natural sciences, final school examination grades, work experience, and voluntary work in the social sector. For the selection of medical students, we recommend the use of final school examination grades in combination with special written test results or, in the case of dentistry, a test of manual dexterity. Interviews might be beneficial to emphasize the importance of non-academic skills and to strengthen the ties of students to their faculty.

Prediction of practical performance in preclinical laboratory courses – the return of wire bending for admission of dental students in Hamburg

Although some recent studies concluded that dexterity is not a reliable predictor of performance in preclinical laboratory courses in dentistry, they could not disprove earlier findings which confirmed the worth of manual dexterity tests in dental admission. We developed a wire bending test (HAM-Man) which was administered during dental freshmen’s first week in 2008, 2009, and 2010. The purpose of our study was to evaluate if the HAM-Man is a useful selection criterion additional to the high school grade point average (GPA) in dental admission. Regression analysis revealed that GPA only accounted for a maximum of 9% of students’ performance in preclinical laboratory courses, in six out of eight models the explained variance was below 2%. The HAM-Man incrementally explained up to 20.5% of preclinical practical performance over GPA. In line with findings from earlier studies the HAM-Man test of manual dexterity showed satisfactory incremental validity. While GPA has a focus on cognitive abilities, the HAM-Man reflects learning of unfamiliar psychomotor skills, spatial relationships, and dental techniques needed in preclinical laboratory courses. The wire bending test HAM-Man is a valuable additional selection instrument for applicants of dental schools.