The mechanisms of control of the TMEM16A channel by the lysosomal NPC1 protein: a new role for the lysosome in the control of cell excitability
Lead supervisors: Prof. Paolo Tammaro
Co-supervisor: Prof. Fran Platt
Commercial partner: Autifony Therapeutics
Ion channels are transmembrane proteins that form pores, allowing charged ions to cross the hydrophobic environment of the cell membrane. Most ion channels form proteinaceous water-filled pores. The TMEM16A anion channel is an exception as its pore has extensive regions directly exposed to plasmalemmal lipids. Thus, TMEM16A may function as a “lipid sensor” by coupling changes in the lipid composition of the membrane with cell electrical activity.
Lysosomes are organelles that actively modulate trafficking of lipids to/from the plasma membrane. Crucial in this process is the lysosomal lipid-binding protein NPC1. Mutations of NPC1 lead to Niemann-Pick disease Type C (NPC), characterized by severe progressive neurodegeneration (‘childhood Alzheimer’s’) and cerebral vascular impairment. The TMEM16A channel is highly expressed in cerebral pericytes, cells that surround capillaries and control local blood flow within the brain. Alterations in TMEM16A function in pericytes occurs in ischaemic stroke and potentially in Alzheimer’s (J Clin Invest. 2022 132:e154118; Trends Pharmacol Sci. 2022 43:712-725.).
The labs of Profs Tammaro and Platts (the academic supervisors for the project) have unexpectedly discovered that genetic ablation of NPC1 or pharmacological inhibition of the NPC1 protein strongly potentiated TMEM16A currents in mammalian cell lines due to altered lipid homeostasis caused by loss of NPC1 function (unpublished). We hypothesise that potentiation of the TMEM16A current may lead to pericyte constriction and cerebral microvascular under-perfusion in NPC disease.
The project falls squarely within the MRC remit of world-leading research in ‘Molecular and cellular medicine’ and ‘Neurosciences and mental health’. The project promises to (i) elucidate the cellular mechanisms that link NPC1 dysfunction to TMEM16A activation, (ii) explore the influence of TMEM16A potentiation on cerebral microvascular blood flow in murine models of NPC disease and (iii) examine the potential for pharmacological amelioration of the condition using novel TMEM16A modulators produced by the industrial partner Autifony. This cross disciplinary project will therefore shed light on how the lysosome may affect cell excitability enhancing our understanding of the basic biology of this organellar system. From a disease biology and pathophysiological perspective, it will also enable the partners to build the case for drug discovery approaches to develop new therapeutic avenues for NPC disease, a debilitating disorder with currently limited treatment options. The results of this work will also have relevance to the development of novel therapeutics for more prevalent, but equally challenging and burdensome diseases, such as vascular dementia and Alzheimer’s.
Apply using course: DPhil in Pharmacology
