Metabolic dysregulation in ALS/FTD:

An early clinical feature of ALS is an imbalance in energy homeostasis, which leads to an overall energy deficit. Due to the high energy demands and impaired glucose metabolism that occurs in ALS, there is a metabolic switch from glucose to lipids for energy production in the central nervous system. The Sephton team is investigating the causes and impacts of this metabolic switch in ALS/FTD and testing therapeutic strategies to restore energy homeostasis. This research topic has positions available for post-doctoral fellows and doctoral students: 

Neuron-glial interconnectivity:

Neuron-glia interactions have important roles in several processes including synapse formation, neurotransmission, and maintenance of energy status. Glia also serve as the resident immune cells of the central nervous system, responding to damaged motor neurons by first acting in a protective manner, but sustained activation of glia promote damage to neurons through neuroinflammation. The Sephton team is investigating the switch of glia from protective to toxic, the impact on synapses and therapeutic targeting of neuroinflammatory pathways to decrease inflammation to restore synaptic homeostasis. 

Local translation and synaptic plasticity:

Local protein translation is a major process involved in sustaining the integrity of dendrites and spines and it critically regulated through activation of the mammalian target of rapamycin (mTOR) signaling pathway. Importantly, one of the earliest pathological features of ALS and FTD is synaptic loss and several familial gene mutations are linked with proteins involved in RNA metabolism and protein synthesis. The Sephton team is investigating how the mTOR pathway is affected in ALS/FTD and the implications of this pathway on the regulation of local translation through modulation of RNA-binding protein activity. 

Funding sources: