The role of neurotrophic B-Raf in Spinal Muscular Atrophy motor circuit pathology and beyond

• Applicant: Dr. Niko Hensel
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 536201542

Spinal Muscular Atrophy (SMA) is a monogenic disease which is caused by low levels of the Survival Motor Neuron (SMN) protein. Next to a degeneration of the lower motor neurons in the spinal cord, the lack of SMN affects the integrity of the whole motor circuit, including dorsal root ganglia (DRG) neurons, DRG fibers, central synapses at the motor neuron cell bodies and the neuromuscular junction (NMJ). However, the underlying molecular mechanisms leading to disease remain elusive. In a recent PNAS paper, we reported a reduced protein expression of the neurotrophic signaling hub B-Raf in SMA models and patient cells, and further that a B-Raf restoration rescued motor neuron numbers in a nematode SMA model. Here, we extend these findings to DRG neurons which indicates an involvement of this pathway in SMA motor circuit pathology beyond motor neuron degeneration. Therefore, we propose an experimental program which evaluates motor circuit pathology in a mammalian SMA mouse model after B-Raf restoration (objective I), explores the mechanisms which lead to B-Raf reduction in SMA (objective II), and evaluates the interaction between changed B-Raf expression and neurotrophic upstream signalling (objective III). The outcomes will contribute to mechanistic knowledge of motor neuron circuit pathology in SMA as well as to novel insights in neuron specific B-Raf signaling. Current SMN-enhancing drugs have limited effects and future combinatorial treatment regimens will rely on a detailed understanding of the SMA pathology and identification of targets downstream of the SMN protein.

• DFG Programme: Research Grants
• International Connection: Canada
• Cooperation Partner: Professor Dr. Rashmi Kothary
• Co-Investigators: Professor Dr. Peter Claus; Dr. Natalia Rodriguez-Muela