My group is interested in elucidating pathways regulating immune cell function and how their alterations affect ageing and neurodegenerative diseases. In particular, we are interested in understanding the function of the voltage-gated proton channel HVCN1 in immune responses, as well as signalling pathways that regulate inflammation in microglia (summary in Fig. 1).
There is only one mammalian voltage-gated proton channel, HVCN1. It works to relieve intracellular acidification and membrane depolarization, letting protons out of the cell following their chemical gradient. In doing so, it sustains the production of reactive oxygen species (ROS) by the enzyme NADPH oxidase (Fig. 2). We were the first to describe HVCN1 role in regulating B cell responses (Capasso et al, Nat Immunol, 2010). HVCN1 loss causes a strong impairment of antibody responses, due to reduced B Cell Receptor signaling. This is due to diminished ROS production by the NADPH oxidase: fewer ROS mean they are no longer able to oxidase and therefore inhibit phosphatases involved in B Cell Receptor signalling. We also described a splicing variant of HVCN1, shorter at the N-terminus, which is able to mediate larger currents and it is upregulated in circulating B cell malignancies such as Chronic Lymphocytic Leukaemia (Hondares et al., PNAS, 2014). Nonetheless, proton channels in B cell malignancies appear to play multiple roles, as we describe in a manuscript in preparation. In myeloid cells, HVCN1 also sustains NADPH oxidase activity, however, its role in cells implicated in the pathogenesis of Alzheimer’s disease, such as microglia and neutrophils, remains to be elucidated. We combine in vivo and in vitro studies to elucidate the impact of HVCN1 loss on this devastating neurodegenerative disease, in order to assess its potential as a therapeutic target.
Since ageing is the greatest risk factor for the development of neurodegenerative diseases, we study signalling pathways altered in ageing in immune cells and their impact on neurodegeneration. Aged microglia, the immune cells of the brain, are characterized by an increased ability to respond to inflammatory stimuli, a process known as microglia priming. We have established that alterations in the mTOR pathway occur with age and this is partly responsible for microglia priming (Fig. 3).