Spatio-functional cellular interplay in peripheral nerve diseases

ongoing

Neuromuscular disorders belong to the most common but least treatable neurological conditions and are caused by defects in cell types that together build the neuromuscular unit – motoneurons and their axons, glial cells and myocytes. Clinically, neuromuscular diseases share an impairment of motor function and the intimate functional relationship of involved cell types suggests overlapping pathological mechanisms. As our current understanding is largely confined to locally isolated processes, the present AxoMyoGlia proposal will undertake the ambitious approach to elucidate the spatial dimensions of the molecular interplay among the key cellular players of the neuromuscular unit. By taking demyelinating peripheral neuropathies as a powerful model system, I aim at unravelling basic principles of how local glial impairment propagates malfunction within the neuromuscular unit, including potential remote axon and muscle feedback mechanisms. To this end, I will employ neuropathic mouse models and generate a holistic transcriptional cellular interactome of the diseased neuromuscular unit at single cell resolution level. With milli- to nanometer imaging precision, this interactome will be extended to the first visualization of the spatial relation between glial and axonal dysfunction along the entire longitudinal dimension of the nerve. In order to untangle local and distant causes from consequences, I will develop an innovative mouse model that will offer the unprecedented option to specifically induce and examine the global consequences of locally restricted glial neuropathy at any position in the neuromuscular system. With its pioneering multimodal approach to converge different areas of neuromuscular research, AxoMyoGlia aims at uncovering general pathological mechanisms at the interface of basic neuroscience and applied neurology - that will be highly relevant for therapeutic advance in neuromuscular diseases and related disorders of the central nervous system.