Andreas Kottmann

Andreas Kottmann, Ph.D.

Assistant Professor

 Motor Neuron Center
Russ Berrie Building, 5th Floor
Tel 212-851-5196
Email 

Specialization

Regulation of Cellular Responses to Physiological Stress in Motor Neurons

RESEARCH THEME

Our lab focuses on the study of the mechanisms, which sense and respond to physiological stress in neurons. A corruption of these processes is thought to occur early in the cascade of events that lead to the eventual neuro-degeneration observed in many neurological diseases. We hope that our research will contribute to develop novel pharmacological strategies that aim to protect vulnerable neurons from degeneration in pathological conditions. We used a candidate gene approach to model early aspects of motor neuron stress and dysfunction in mice. Wolframin (wfs1) is an endoplasmatic reticulum (ER) resident, transmembrane protein, which is involved in the regulation of intracellular Ca++ homeostasis and which is also essential for the mounting of a cell autonomous, physiological stress response. We produced mice with a genetic ablation of wfs1 in motor neurons. These mice develop a progressive neurological dysfunction cumulating in severe respiratory arrhythmia, muscle atrophy and premature death. Despite a partial denervation of somatic muscles we do not observe motor neuron loss in these mice. However, motor neurons in the absence of wfs1 have a marked dilation of the ER and exhibit cytoplasmic and ER invaginations into the cell nucleus. The cellular pathology indicates a persistent increase in cellular stress levels in motor neurons in the absence of wfs1. We will exploit this in vivo model of cellular motor neuron stress to investigate motor neuron specific stress response pathways. In particular our lab has begun to produce embryonal stem cells with homozygous ablations of wfs1 from which we will differentiate motor neurons in vitro. Wfs1 mutant and wild type, in vitro differentiated, motor neurons will serve as the cellular substrate for the biochemical and cell biological analysis of motor neuron specific stress response pathways. This work will help us to devise functional complementation assays for the high throughput selection of compounds, which are able to induce appropriate stress response pathways in vulnerable motor neurons under conditions of physiological and pathological cell stress.