Lay Summary:
Lysosomes are the garbage disposal and recycling system of our cells. Altered lysosome function is associated with numerous neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Hereditary Spastic Paraplegia, although we do not know exactly how. My work has demonstrated that not all 'lysosomes' in a neuron (nerve cell) are the same. Those in the cell body of neurons differ from those in nerve fibres. The latter do not have the enzymes needed to degrade material. Certain mutations or disease conditions also seem to affect the populations differently. The lab’s investigations will thus focus on what makes these lysosomal pools different, what regulates each of them, how do they interact with one another and what else, in addition to those enzymes, is different about their content. We will also determine which of these defining features change (and how they do so) during specific disease conditions. Lastly, in the long term, we will test if these changes can be reversed with the ultimate hope of developing therapeutic strategies for neurodegenerative diseases.
Detailed Technical Description:
Lysosomes are degradative organelles, whose function is critical for protecting long-lived cells such as neurons from the build up of misfolded proteins and damaged organelles.Altered lysosome function is associated with numerous neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Hereditary Spastic Paraplegia (HSP). However, the precise molecular mechanisms underlying their involvement are not known. Nor are the mechanisms of lysosome formation and function in neurons, well understood. My post doctoral work investigating the cell biology of amyloid plaques in Alzheimer’s disease led to the discovery of an unexpected heterogeneity of neuronal lysosomes: unlike lysosomes in neuronal cell bodies, those in neurites are deficient in luminal proteases and thus lack degradative capacity. This has important consequences for protein and organelle-turnover in different parts of a neuron. Thus understanding the molecular basis of neuronal lysosome heterogeneity is important for fundamental neuroscience as well as for understanding neurodegenerative disease mechanisms. Furthermore, I found that perturbing transport (and maturation) of the axonal pool specifically exacerbated Alzheimer's plaque pathology. This implies that the different lysosomal populations may be differentially sensitive to insults and /or mutations.
My laboratory now aims to understand how these distinct lysosomal pools form, interact and function in the different parts of the neuron and how their dysfunction causes and/or exacerbates neurodegenerative diseases. Using a multidisciplinary approach (high resolution imaging, proteomics and CRISPR Cas9-mediated perturbation in primary mouse neurons and IPSC-derived neurons), we will identify the defining molecular composition of these distinct lysosomal populations, factors that uniquely (or differentially) regulate them and the molecular basis for their differential responses to stresses. The lab also interrogates mechanisms underlying lysosome dysfunction in Alzheimer’s Disease and hereditary spastic paraplegia (focusing on a subgroup of HSPs where the genes encode lysosome-localized proteins). These studies will yield novel insight into the pathological mechanisms of diseases and identify molecular pathways that are potentially amenable to therapeutic intervention.