How can cellular degradative pathways be manipulated for therapeutic benefit?
Lysosomes are acidic cellular organelles that digest pathogens, eliminate damaged cellular material and also control the levels of receptors that regulate cell proliferation and motility.
Lysosome dysfunction has been implicated in multiple age-related neurodegenerative diseases where toxic material accumulates in the eye and in the brain. Exciting new advances have shown that cells can respond to lysosome dysfunction by increasing the production of lysosomal proteins but how these proteins are packaged into new lysosomes and how the cell disposes of the old or dysfunctional lysosomes is unclear. The retinal pigment epithelium (RPE) is a layer of pigmented cells at the back of the eye that supports the photoreceptors. One of its critical functions is the daily degradation of spent photoreceptor outer segments, giving the lysosomes of these cells a huge degradative burden. With age and in age-related macular disease debris accumulates at the back of the eye, indicating that the lysosomes of the RPE have become overloaded or dysfunctional. We use cultured RPE cells to determine how these cells respond to lysosome dysfunction, how old and dysfunctional lysosomes are disposed of and how new lysosomes are made. We use live-cell imaging and electron microscopy to identify the trafficking steps and proteomic and genetic approaches to identify the molecular machinery underlying these processes. We hope to identify new pathways for therapeutic intervention that will upregulate the degradative capacity of the cell and limit the accumulation of toxic material in the eye and the brain.
Trafficking to the lysosome is also an important way to control the signalling of growth factor receptors. The EGF receptor is overexpressed in multiple human cancers and is an important target for cancer therapies. Some anti-EGF receptor therapeutic antibodies promote the delivery of the receptor to the lysosome for degradation whilst others block receptor activity or promote antibody-dependent cellular cytotoxicity. We are investigating ways in which the trafficking of EGF receptors can be manipulated to improve the therapeutic response to antibodies and chemotherapies.
The image shows cultured RPE cells incubated with fluorescent dextrans (red) that get taken up and delivered to lysosomes and Lysotracker (green) which stains acidic compartments. The inset is an electron microscopy image of a lysosome.