ForInter

BAVARIAN RESEARCH ASSOCIATION INTERACTION OF HUMAN BRAIN CELLS

Generation and validation of induced pluripotent stem cells for modeling of motor neuron diseases

Field of work:

Motoneuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) constitute a major challenge for modern biomedicine since causal therapies are still lacking. The genetic basis of ALS and SMA has been elucidated in the last two decades, but the molecular mechanisms underlying motoneuron disease are still largely unknown. Cell culture models derived from mouse models of SMA and ALS point to specific defects in axon growth and maintenance. However, these models are limited due to the low number of cells that can be isolated from individual mouse embryos, and biochemical and functional studies are only possible with highly sensitive methods. The first part of the project aims to optimize and validate techniques for generation and differentiation of iPS cells by comparison with primary motoneurons from corresponding mouse models. A second part of the project focusses on the molecular mechanisms that mediate altered axon growth and maintenance in motoneurons from mouse models and patients with motoneuron disease. We will focus in particular on mechanisms for altered stability of the axonal cytoskeleton and presynaptic structures for synaptic release mechanisms at neuromuscular endplates. Comparative studies with iPS cells from patients with Morbus Parkinson shall reveal whether axonal alterations for transport of mRNAs are a common feature in neurodegenerative disorders.

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