The role of Ighmbp2 during motor circuit pathology in movement disorders

• Applicant: Dr. Christian Simon
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 536856302

Motor circuit pathologies are the main cause for movement disorders. While certain aspects of motor circuit pathology have been deciphered, very little is known pertaining to the incurable diseases spinal muscular atrophy with respiratory distress (SMARD1) and Charcot-Marie-Tooth 2 (CMT2). Both diseases can be caused by a reduced amount of the DNA/RNA-binding protein Ighmbp2. The neuromuscular degeneration (NMD) mouse line is an established model for SMARD1 and CMT2 with motor impairment caused by a mutation of the Ighbmp2 gene. Our preliminary data shows selective vulnerability of spinal motor circuits, including motor neuron death and loss of proprioceptive synapses. In this proposal, we will investigate the degree and cause of motor circuit pathology in NMD mice. We will selectively virally restore Ighmbp2 function in motor neurons or proprioceptive neurons to determine the cellular driver for motor circuit pathology. Next, we will investigate motor neuron dysfunction by patch-clamp recordings. Finally, we will perform viral and genetic manipulation of selective proteins to identify the cause of motor neuron death. This proposal will give detailed insights of the pathological events which lay the ground for future mechanistic and therapeutic strategies for SMARD1, CMT2 and possibly other movement disorders.

• DFG Programme: Research Grants