In this online seminar William Hancock-Cerutti, MD-PhD candidate at Pietro De Camilli’s lab (Yale University), Chantelle Evans, postdoc at Erika Holzbaur’s lab (University of Pennsylvania) and Louisa Wang, postdoc at Gerold Schmitt-Ulms’s lab (University of Toronto) present on “Cell Biology and Neurodegeneration”.

William’s presentation centres around VPS13C, a Parkinson’s disease protein whose cellular function is very poorly known (“Cell Biology of VPS13C/PARK23, a Novel Lipid Transport Protein”). Genetic variation in VPS13C (PARK23) is a risk factor for Parkinson’s disease (PD), and biallelic loss-of-function mutations result in severe, early-onset PD. Work from William’s group and collaborators demonstrates that the VPS13 family encodes a novel class of lipid transfer proteins localized to inter-organelle contact sites, where they are thought to function as bridges to transfer lipids between membranes via a large hydrophobic channel. VPS13C localizes to contact sites between the endoplasmic reticulum and late endosomes/lipid droplets, and its loss leads to perturbations in lysosomal lipid homeostasis that may have implications for PD pathogenesis.

Chantelle talks about the dynamics of mitochondrial clearance by autophagy in neurons (“Investigating the Spatiotemporal Dynamics of Parkin-Dependent Mitophagy in Neurons”).
Damaged mitochondria are removed from the cell via mitophagy. This pathway may be important for neuronal homeostasis, as mutations in pathway components cause PD and ALS. Chantelle and her collaborators used live imaging to investigate the spatiotemporal dynamics of mitophagy in primary neurons following mild oxidative stress. Mitophagy-associated proteins rapidly translocate to depolarized mitochondria and mitochondria were sequestered in autophagosomes within an hour of damage. Surprisingly, the downstream degradation of engulfed mitochondria was delayed, primarily due to slow acidification of the resulting mitophagosomes. Expression of an ALS-associated mutation disrupted mitochondrial network function, and stress exacerbated this effect. These results suggest that slow turnover of damaged mitochondria may increase neuronal susceptibility to neurodegeneration.

Finally, Louisa presents her research on “Using Genetic Editing to Study Neurodegenerative Diseases”. Using CRISPR-Cas9-engineered cells with inducible tau expression and mass spectrometry-based interactome studies, Louisa and her group found that a single point mutation (P301L) in tau can reduce its interaction with not just one, but a family of non-muscle myosins by as much as 6 times compared with wildtype tau in two cell models consistently. They validated that the preferential interaction of non-muscle myosins to wildtype tau depends on active ATPase structure or function, which may be reduced in mutant P301L mice. Tau also seems to stabilize the expression of non-muscle myosins.