Cellular Quality Control and Organelle Dysfunction
Four Fellows are working on projects to investigate the breakdown and repair of intracellular maintenance systems, seeking to describe molecular pathways underlying mitochondrial homeostasis, lysosomal remodeling, endolysosomal trafficking, and ciliary signaling. Alterations in these pathways may serve as potential biomarkers of Parkinson’s disease. These researchers will determine where cellular quality control fails and how to rescue it, ultimately halting disease progression.
Odetta Antico, PhD
Project Title: Untangling PINK1–Tau crosstalk and co-morbidity mechanisms in Parkinson’s disease
Home Team: Alessi (Muqit Lab)
Host Team: Harper (Harper Lab)
Institution: University of Dundee
Project Summary: Emerging evidence links Tau-driven mitochondrial dysfunction to Parkinson’s disease. This project tests the hypothesis PTEN-induced kinase 1 (PINK1) and Tau interact in a feed-forward loop in which PINK1 deficiency drives pathogenic Tau changes, while Tau impairs PINK1-dependent mitochondrial homeostasis. Building on preliminary evidence connecting PINK1 loss to human Tau phosphorylation at phosphoSer214 (pSer214) and leveraging relevant mouse models, including a novel phosphomimetic PINK1-TESE knock-in mouse, this project aims to define the Tau post-translational modification code and interactome under PINK1 deficiency, quantify in vivo mitophagy thresholds and regional flux, and map pS65-Ubiquitin and pSer214-Tau dynamics as early biomarkers. Integrated proteomics, biochemistry, and imaging will reveal mechanistic nodes and test PINK1 enhancement as a disease-modifying strategy.
Bishal Basak, PhD
Project Title: Targeting Rubicon to restore lysosomal and autophagic health in LRRK2-driven Parkinson’s disease
Home Team: Hurley (Holzbaur Lab)
Host Team: Alessi (Alessi & Muqit Labs)
Institution: University of Pennsylvania
Project Summary: Hyperactive mutations in leucine-rich repeat kinase 2 (LRRK2), the most common genetic cause of Parkinson’s disease, impair lysosomal acidification and autophagic turnover, leading to neuronal vulnerability. Rubicon, a neuron-enriched protein, has recently been identified as a key negative regulator of lysosomal and autophagic function, particularly in neurons. This project will define the mechanistic role of Rubicon in lysosomal remodeling and autophagy, and determine whether its inhibition can restore degradative defects caused by LRRK2 hyperactivity. Broadly, this study will establish Rubicon as a critical node in neuronal quality control and highlight its potential as a target for restoring degradative capacity and resilience in Parkinson’s disease.
Amanda Bentley-DeSousa, PhD
Project Title: The Parkinson’s disease kinase LRRK2 regulates lysosome damage
Home Team: De Camilli (Ferguson Lab)
Host Team: Harper (Harper Lab)
Institution: Yale University School of Medicine
Project Summary: Lysosome damage is a critical hallmark of Parkinson’s disease, with many Parkinson’s disease-relevant proteins playing a role. Environmental, genetic, and cellular stressors cause the lysosomal activation of LRRK2, with hyperactivation enhancing Parkinson’s disease risk. Previous work identified a key signaling pathway involving the conjugation of ATG8 to single membranes and gamma-aminobutyric acid receptor-associated protein as a critical means of activating LRRK2, linking diverse stress inputs to disease pathways. Preliminary data show that this increased LRRK2 activity enhances lysosomal damage and TANK-binding kinase 1 (TBK1)–Rab7 signaling. This project integrates expertise in cell biology and proteomics to define novel LRRK2 substrates and uncover the link between LRRK2 and TBK1–Rab7 signaling, in an effort to elaborate on therapeutic strategies in Parkinson’s disease.
Prosenjit Pal, PhD
Project Title: Decoding the role of endolysosomal and ciliary crosstalk in Parkinson’s disease pathogenesis
Home Team: Alessi (Alessi Lab)
Host Team: De Camilli (Ferguson Lab)
Institution: University of Dundee
Project Summary: Emerging evidence links defects in endolysosomal trafficking and aberrant ciliogenesis to Parkinson’s disease, though their crosstalk is unclear. One hypothesis is that hyperactive Parkinson’s disease-causing proteins, such as LRRK2 and vacuolar protein sorting 35 (VPS35), impair this interaction, disrupting ciliary signalling essential for dopaminergic neuron survival. Using mutant mouse models, mouse embryonic fibroblasts, human iPSC-derived neurons, and advanced tools—including proteomics, lipidomics, live-cell lipid biosensors, and super-resolution microscopy—this project will dissect how these pathways drive neurodegeneration, aiming to uncover mechanisms, identify biomarkers, and highlight novel therapeutic targets that could halt Parkinson’s disease progression.
