Mitochondrial protein SFXN3 as a novel target in neurodegenerative diseases
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Date
17/12/2021Author
Ledahawsky, Leire Maddalen
Metadata
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.