Developmental alterations driving on selective vulnerability in spinal muscular atrophy and amyotrophic lateral sclerosis

• Applicant: Dr. Natalia Rodriguez-Muela
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Developmental Neurobiology ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537569134

How certain neuronal subpopulations become highly vulnerable upon ubiquitously expressed disease-causing mutations is an unresolved fundamental question in neuroscience that is halting the discovery of efficacious treatments. This striking selective vulnerability also occurs in the most common motor neuron diseases (MNDs), spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), where similar questions remain open. Why are MNs primarily affected, and why do not all MNs degenerate to the same degree? Do some MNs harbor intrinsic marks that make them prone to degenerate? Do these diseases have a neurodevelopmental component that triggers the onset in the postnatal/adult life? Distinct vulnerability patterns of specific motor units have been reported for SMA and familial forms of ALS (fALS) However, the molecular underpinnings and the order of events that lead to neuronal death remain unclear. This study hypothesizes that such distinct degenerative patterns are not stochastic but primed by specific factors. The most common neurodegenerative diseases (NDs) have a late onset, thus, it is not surprising that the developmental aspect of these diseases has been ignored in favor of a post-mitotic focus. However, recent evidence suggests unanticipated developmental alterations in NDs. In contrast to the current approaches aimed at investigating ND progression from a post-symptomatic perspective, we will examine SMA and fALS from a development angle and will test whether specific neuronal progenitors experience defects during specification that cause a vulnerability imprint in mature neurons. To this end, entirely novel isogenic patient-derived spinal cord organoid models of SMA and fALS will be used. This proposal aims first at exploring how SMA and fALS penetrant mutations impact the molecular diversity and biology of distinct neural progenitors and MN subtypes during their earliest developmental phases, as well as at unraveling whether those potential developmental abnormalities are shared or disease/mutation-specific. Given the extension of the proposed plan, the remaining part of the study will concentrate on SMA. A second aim will focus on unravelling the molecular mechanisms underlying neuronal/MN progenitor subtype specification defects upon SMN deficiency. The discoveries made from these aims will reveal whether pathological developmental states, emerging from mutated SMN1 or SOD1/TARDP genes, exist in the patients prior to symptoms that could be potentially treated at early stages to halt the emergence of degeneration. Finally, a third aim will elucidate whether SMA MN subpopulations are differentially vulnerable to diverse stressors. The acquired knowledge would enable the design of new potential therapies targeting specific pathways in a cell subtype- or disease-phase manner. All together, the proposed study will lay the foundation for potentially revisiting the fundamental biology behind SMA and fALS etiology and treatment.

• DFG Programme: Research Grants