Current Research

(A) AnkyrinG: A molecular determinant of neuronal polarity

Neurons are highly polarized cells that are capable of developing and maintaining two highly distinct types of cell processes: (I) the axon and (II) dendrites. The mechanisms that underly the development and maintenance of this axo-dendritic polarity are largely unknown. Earlier in vitro studies suggest that a membrane-associated diffusion barrier, localized in the axon initial segment (AIS), contributes to the maintenance of axo-dendritic polarity. We hypothesized that the AIS-specific membrane adapter protein ankyrinG plays a major role for the function of the AIS-specific diffusion barrier thereby maintaining of neuronal polarity. This hypothesis was tested by studying neuronal polarity in mice with a cerebellum-specific knock out for ankyrinG. Strikingly, cerebellar axons of these animals develop a number of hallmark features normally associated only with dendrites. Most importantly, these axons are endowed with tiny protrusions closely resembling dendritic spines. Similar to their dendritic counterparts these aberrant axonal spines possess postsynaptic glutamatergic receptors and are contacted by presynaptic glutamatergic boutons as revealed by combined light- and electronmicroscopy. We conclude that anykrinG plays a key role for maintaining appropriate axo-dendritic polarity in vivo. Currently, we are using several in vitro and in vivo paradigms to further unravel the fundamental cellular and molecular mechanisms of ankyrinG-mediated neuronal polarity.

Schultzfig1
Fig. 1: AnkG-deficiency causes PC axons to develop spines in vivo. (A–C) The morphology of PC in ankG-/- mice is visualized by anti-calbindin D28K labeling. (A) At low magnification, principal features of axo-dendritic polarity are preserved. PC dendrites branch in the molecular layer (ML), PC somata are aligned in the Purkinje cell layer (PCL), and PC axons (arrow) traverse the granule cell layer (GCL) en route to the white matter (WM). (B) Higher magnification of framed area in A. Three PC axons originating from their parental cell body are depicted. Two of them (arrowheads) exhibit a conspicuous spiny appearance. By comparison, the third axon (arrow) shows a smooth surface. (C) Close-up view of framed area in B. The PC axon gives rise to numerous spines (arrowheads). (D) 3-dimensional morphology of a spiny PC axon. (Scale bars: A, 100µm; B, 20µm; C and D, 2µm.) Adapted from Sobotzik et al., Proc Natl Acad Sci U S A (2009) 106:17564-17569

(B) Activation of NF-KappaB in the axon initial segment

The transcription factor NF-KappaB plays a major role for regulating the survival of neurons in the central and peripheral nervous system. Recently, we discovered a surprisingly selective enrichment of key elements of the classcial activated NF-KappaB cascade in the axon initial segment (AIS). This includes phosphorylated IkappaB alpha (see figures) as well as activated IkappaB-Kinase. These findings point to a novel role of the AIS as a specific compartment involved in NF-KappaB activation.

Schultzfig 2
Fig. 2: Enrichment of phosphorylated IkappaB alpha (red) in the axon initial segment of neurons in the rat cerebral cortex (left side) and in a primary neuronal culture (middle). The green labeling depicts the somatodendritic neuronal compartment. Specific enrichment of phosphorylated IkappaB alpha (red) in the axon initial segment of an organotypic hippocampal slice culture (right side). Adapted from Schultz et al., Mol. Cell. Neurosci. 33 (2006) 68–80)

(C) Research on Tauopathies

The abnormal aggregation of the microtubule-associated protein tau plays a central pathogenic role in a number of neurodegenerative diseases of the human brain, together referred to as the „tauopathies“. The most important member of these diseases is Alzheimer´s disease. The development of therapeutic approaches for curing tauopathies is significantly hampered by the lack of an appropriate animal model. Using immunhistochemistry against abnormally phosphorylated forms of tau protein we were able to document a previously unknown form of tau pathology in brains of aged non-human primates (baboons). Based on the close phylogenetic relationship between baboons and the human species, further studies on these changes may complement the work on transgenic mouse models for tau pathology.

Schultzfig3
Fig. 3: Alzheimer-like pathology detected in a 30-yr-old baboon by AT8 immunostaining for abnormally phosphorylated tau protein. Left: Frontal hemisphere section with a conspicuous accumulation of tau patology in the medial temporal lobe. The framed box is shown at higher magnidication on the right side. Right: A dense accumulation of tau pathology is seen in the entorhinal cortex, in the white matter of the perforant pathway, and in the hippocampal formation (F.D.: fascia dentata) Adapted from Schultz et al., J Neuropathol Exp Neurol 2000; 59:39-35

 

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Latest Revision: 2012-08-01
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