The effect of mitochondrial transport and function on synaptic integrity during ageing

Lead Research Organisation: King's College London
Department Name: Clinical Neuroscience


Mitochondria are small membrane-bound organelles that generate ATP(Kann & Kovacs, 2007). ATP is essential for neuronalfunction(Cai & Sheng, 2011), including the filling, release, and recycling of synaptic vesicles (Takeda & Ueda, 2017) and the maintenance of calcium homeostasis (Werth & Thayer, 1994). Efficient mitochondrial transport and proper mitochondrial distribution is critical to ensure mitochondria can service all parts of the neuron, especially highly energy-dependent regions such as the synapses (Cai & sheng, 2011). Furthermore, mitochondrial function and transport is important for the trafficking of other cargo, as intracellular transport is ATP-dependent (Zala et al., 2013).The Vagnoni lab found that mitochondrial transport decreases with ageing (Vagnoni et al., 2016), using a novel method to image cargo transport in live Drosophila by imaging the sensory neuron axons within the wing (Vagnoni & Bullock, 2016). Furthermore, the lab showed that experimentally elevating levels of mitochondrial transport in aged Drosophila neurons (by stimulating thecAMP/ PKA pathway) has a protective effect, reducing oxidative stress levels (Vagnoni & Bullock, 2018). The lab has preliminary evidence that amyloid precursors protein (APP), which is also transported by the kinesin motor, shows decreased trafficking during ageing. However, it is not clear whether this is linked to the defective mitochondrial transport effect. Synapses are junctions between a presynaptic neuron and a postsynaptic cell, usually another neuron (Sudhof, 2018). Synapses are essential for neurotransmission -the diffusion of neurotransmitters across the synapse and their subsequent detection by receptors on the postsynaptic cell surface (Sudhof, 2018). Cell adhesion molecules neurexin (on the presynaptic cell membrane) and neuroligin (on the postsynaptic cell membrane) tether the pre-and post-synaptic cells together, making them particularly important for synapse formation and maintenance (Craig & Kang, 2007). Studies have shown that neurexin and neuroligin are transported through neurons much like mitochondria, using the microtubule network and kinesin/ dynein motor proteins (Kneussel, 2011; Puthanveettil et al., 2008). Indeed, knockdown of kinesin-1 stops neurexin moving towards synapses, causing it to accumulate at the soma and axon initial segment (Neupert et al., 2015). Studies have shown that synaptic dysfunction occurs during ageing (Morrison & Baxter, 2012) and is a hallmark of several neurodegenerative diseases (Wishart et al., 2006). Neuroligin and neurexin have been shown to interact with amyloidogenic proteins, present in Alzheimer's disease, indicating an functional role for synapses in Alzheimer's pathogenesis (Brito-Moreira et al., 2017). In conclusion, it is clear mitochondria are important for synaptic health. The evidence shows that both mitochondrial transport dysfunction and synaptic dysfunction are associated with ageing. However, there are several unknowns. No study has unequivocally shown how defective mitochondrial transport affects synaptic stability, or the transport of other cargo like neurexin and neuroligin, during ageing. Furthermore, we do not know how defective mitochondrial transport affects the trafficking of neurodegenerative disease-relevant proteins like APP during ageing. These questions are important as they would enable us to better understand the factors causing age-related decline in synapse function, a common feature of brain dysfunction.


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
MR/N013700/1 30/09/2016 29/09/2025
2444948 Studentship MR/N013700/1 30/09/2020 29/09/2024 Ethlyn Lloyd-Morris