Associate Professor - Department of Biology
Loss of protein and organelle homeostasis (proteostasis) is well documented in neurodegenerative conditions, and seems to depend on the progressive pathological decline in the proteolytic activity of two major degradative systems: the ubiquitin-proteasome and the lysosome-autophagy system. While alterations in proteostasis are common in older adults, they seem to be more severe in people that suffer age-related neurodegenerative disease like Parkinson’s Disease (PD) and amyloid lateral sclerosis (ALS). Indeed, promoting proteasome or autophagy activity increases lifespan, and rescues the pathological phenotype of animal models of neurodegeneration, presumably by enhancing the degradation of misfolded proteins and dysfunctional organelles, which are known to accumulate in these models and to induce intracellular damage.
There are several ongoing projects in the lab, which are mainly focused on the beneficial “proteostatic” effect of inhibiting deubiquitinating enzymes (DUBs) UPS14 and USP8.
USP14 is a proteasome-associated deubiquitinating enzyme. We study both the mammalian (USP14) and fly (Drosophila) forms of the enzyme. USP14 is a powerful regulator of the proteasome, which inhibition enhances the activity of the proteasome but also autophagy and mitophagy. Mitophagy in particular is a selective type of Autophagy that contributes to mitochondrial quality control, which is often deranged in neurodegenerative conditions. We investigate the autophagic and mitophagic effect of USP14 inhibition in primary neurons differentiated from pluripotent stem cells of human origin, and in vivo in flies.
Another interesting deubiquitinating enzyme, which activity is correlated to autophagy and mitophagy is USP8. USP8 is an endosome-associated DUB that regulates the ubiquitination, trafficking, and lysosomal degradation of several plasma membrane proteins. We found that inhibition of USP8 enhances Autophagy and Mitophagy via an unknown molecular mechanism, which is currently under investigation in the lab.
In the lab we take an interdisciplinary approach, which combine the use of pharmacological inhibition of these DUBs in neurons of human origin with the generation and analysis of drosophila and mouse strain specifically lacking DUBs protease activity. We use acute, time-resolved models of USP14 and USP8 inhibition in neurons of human origin in conjunction with quantitative global proteomics to investigate the underlying molecular mechanisms of protection.
Cerqueira F. M, von Stockum S, Giacomello M, Goliand I, Kakimoto P, Marchesan E, De Stefani D, Kowaltowski A. J, Ziviani E, Shirihai O. S (2020). A new target for an old DUB: UCH-L1 regulates mitofusin-2 levels, altering mitochondrial morphology, function and calcium uptake. Redox Biology.
Basso V, Marchesan E, Ziviani E (2020). A trio has turned into a quartet: DJ-1 interacts with the IP3R-Grp75-VDAC complex to control ER-mitochondria interaction. Cell Calcium.
Faustini G, Marchesan E, Zonta L, Bono F, Bottani E, Longhena F, Ziviani E, Valerio A, Bellucci A (2019). Alpha-synuclein preserves mitochondrial fusion and function in neuronal cells. Oxidative Medicine Nov 23.
von Stockum S, Sanchez-Martinez A, Corrà S, Chakraborty J, Marchesan E, Locatello L, Da Rè C, Cusumano P, Caicci F, Ferrari V, Costa R, Bubacco L, Rasotto MB, Szabo I,Whitworth AJ, Scorrano L, Ziviani E (2019.) Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction. Life Sci Alliance Apr 15.
Chakraborty J, von Stockum S, Marchesan E, Caicci F, Ferrari V, Rakovic A, Klein C, Antonini A, Bubacco L, Ziviani E (2018). USP14 inhibition corrects an in vivo model of impaired mitophagy. EMBO Mol Med Sep 24.
Basso V, Marchesan E, Peggion C, Chakraborty J, von Stockum S, Giacomello M, Ottolini D, Debattisti V, Caicci F, Tasca E, Pegoraro V, Angelini C, Antonini A, Bertoli A, Brini M, Ziviani E (2018). Regulation of ER-mitochondria contacts by Parkin via Mfn2. Pharmacological Res.
von Stockum S, Marchesan E, Ziviani E (2018). Mitochondrial quality control beyond PINK1/Parkin. Oncotarget. Jan 18.