Impact of α-spectrin mutations on the cytoskeleton and organelle organization in neurodegeneration

Spectrins are an integral part of the submembranous cytoskeleton providing both mechanical scaffolding and organization hub for other proteins in metazoan cells. The importance of spectrins to neuronal health is demonstrated by their association with a wide range of human neurological disorders (spectrinopathies). Currently, more than forty mutations in the gene encoding non-erythroid -spectrin (SPTAN1) are associated with developmental and epileptic encephalopathies, hereditary motor neuropathy (HMN), spastic paraplegia (HSP), and ataxia. The underlying pathomechanisms remain largely unknown. In Drosophila, the highly conserved -spec homolog similarly plays an important role in the nervous system development, as well as in synapse formation, its function and maintenance. Interestingly, synaptic defects associated with loss of -spec can be suppressed via neuronal mitochondria repositioning. Conversely, increased levels of -spec rescue a range of neuronal phenotypes linked to actin-dependent mitochondrial dysfunction in an -synuclein neurodegeneration Drosophila model. These findings suggest that modulating the levels of -spec in neurons might have an important and understudied impact on tuning mitochondrial dynamics and preserving neuronal health. Thus, the goal of my MSCA proposal is to deepen our knowledge on how neuronal actin and spectrin cytoskeleton regulate mitochondria and assess mitochondrial dysfunction at the basis of -spectrinopathies, with a combined use of Drosophila as a model organism, and human iPSC-derived neurons as a platform to translate the findings to human neuronal health and disease. My project will provide insights on whether spectrin-associated mitochondrial dysfunction is a shared or specific feature for HMN, HSP and ataxia-associated spectrin mutants. I will deploy these findings to tailor a pharmacological treatment in the -spectrinopathy neuronal cellular models and develop a therapeutic strategy.