Biology subjects

Magno, L.

Publications and source records attributed to Magno, L..

2 recordsLinked to original sources

bioRxiv2018

Alzheimer’s disease Phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph

Recent Genome Wide Association Studies (GWAS) have identified novel rare coding variants in immune genes associated with late onset AD (LOAD). Amongst these, a polymorphism in Phospholipase C-gamma 2 (PLCG2) P522R, has been reported to be protective against LOAD. PLC enzymes are key elements in signal transmission networks and are potentially druggable targets. PLCG2 is highly expressed in the hematopoietic system. Hypermorphic mutations in PLCG2 in humans have been reported to cause autoinflammation and immune disorders, suggesting a key role for this enzyme in the regulation of immune cell function.\n\nWe confirmed that PLCG2 expression is restricted primarily to microglia in both the healthy and AD brain. Functional analysis of the P522R variant in heterologous systems demonstrated a small hypermorphic effect of the mutation on enzyme function. PLC{gamma}2 is therefore a potential target for modulating microglia function in AD, and a small molecule drug that weakly activates PLC{gamma}2 may be one potential therapeutic approach.\n\nSUMMARYThe PLCG2 P522R variant is protective against Alzheimers disease (AD). We show that PLCG2 is expressed in CNS-resident myeloid cells, and the P522R polymorphism weakly activates enzyme function. These data suggest that activation of PLCG2 and not inhibition could be therapeutically beneficial in AD.

neuroscience↗

bioRxiv2017

Single-Cell Transcriptomic Analysis Of CA1 Inhibitory Neurons

Understanding any brain circuit will require a categorization of its constituent neurons. In hippocampal area CA1, at least 23 classes of GABAergic neuron have been proposed to date. However, this list may be incomplete; additionally, it is unclear whether discrete classes are sufficient to describe the diversity of cortical inhibitory neurons, or whether continuous modes of variability are also required. We studied the transcriptomes of 3663 CA1 inhibitory cells, revealing 10 major GABAergic groups that divided into 49 fine-scale clusters. All previously described and several novel cell classes were identified, with three previously-described classes unexpectedly found to be identical. A division into discrete classes however was not sufficient to describe the diversity of these cells, as continuous variation also occurred between and within classes. Latent factor analysis revealed that a single continuous variable could predict the expression levels of several genes, which correlated similarly with it across multiple cell types. Analysis of the genes correlating with this variable suggested it reflects a range from metabolically highly active faster-spiking cells that proximally target pyramidal cells, to slower-spiking cells targeting distal dendrites or interneurons. These results elucidate the complexity of inhibitory neurons in one of the simplest cortical structures, and show that characterizing these cells requires continuous modes of variation as well as discrete cell classes.

neuroscience↗