Mitochondrial protein SFXN3 as a novel target in neurodegenerative diseases

Abstract

Neurodegenerative diseases are a group of heterogeneous disorders consisting of the progressive degeneration of the nervous system. Despite major scientific advances, most neurodegenerative diseases have no cure. This results in a significant emotional, social, and economic burden across the globe. In the hopes of finding effective therapies, studies have identified synapses as a primary pathological target across various neurodegenerative diseases, including Parkinson’s Disease, Alzheimer’s Disease, Huntington’s Disease and Motor neuron disease. These studies highlight the therapeutic potential of targeting pathways involved in synaptic pathology as a strategy to delay the onset or progression of neurodegenerative diseases. Our lab has investigated proteins downstream of a-synuclein, which is a modulator of synaptic pathology, and Sideroflexin 3 (SFXN3) was identified as a mitochondrial protein that modulates synaptic morphology in vivo. This finding prompted the aims of this thesis: biochemical characterisation of SFXN3; the identification of SFXN3’s molecular interactors and the investigation of its role in neurodegeneration. We showed that the mitochondrial localisation of SFXN3 is conserved between mice and humans. Import experiments also identified SFXN3 as a substrate of the mitochondrial carrier import pathway. Next, to identify molecular interactors of SFXN3, quantitative proteomics on synaptosome-enriched samples identified proteins associated with neurodegeneration and cell death, such as CSPa and uncleaved Caspase-3, downstream of SFXN3. Considering these results, we sought to investigate whether SFXN3 can rescue neurodegeneration in the context of neurodegenerative diseases. To do so, levels of Sfxn3 were manipulated in Drosophila models of Parkinson’s Disease. The results showed that overexpression of Sfxn3 could rescue neurodegenerative phenotypes, such as the loss of dopaminergic neurons. To investigate whether, conversely, the loss of Sfxn3 triggers neurodegeneration, brain morphometry and western blotting of mitochondrial health proteins was performed on 1-year-old Sideroflexin 3 knockout (Sfxn3-KO) mice. The results obtained showed no differences between wild-type (WT) and Sfxn3-KO mice in any of the parameters measured, suggesting that the loss of Sfxn3 is not sufficient to trigger neurodegeneration in older mice. In summary, these results demonstrate the potential of SFXN3 as a novel target in the treatment of various neurodegenerative diseases that primarily target the synapse.