Catalog
ASAP is committed to accelerating the pace of discovery and informing a path to a cure for Parkinson’s disease through collaboration, research-enabling resources, and data sharing. We’ve created this catalog to showcase the research outputs and tools developed by ASAP-funded programs.
Toward a standard model for autophagosome biogenesis
Two papers in this issue resolve a long-standing obstacle to a “standard model” for autophagosome biogenesis in mammals.
Teams
Themes
Mitochondrial degradation: Mitophagy and beyond
Published: The molecular signals driving varied pathways are discussed, including the cellular and physiological contexts under which the different degradation pathways are engaged.
Teams
Themes
A RAB7A phosphoswitch coordinates Rubicon Homology protein regulation of Parkin-dependent mitophagy
Published: Structural and functional data support a model in which the TBK1-dependent phosphorylation of RAB7A serves as a switch, promoting mitophagy by relieving Rubicon inhibition and favoring Pacer activation. View original preprint.
Teams
Themes
Structural pathway for class III PI 3-kinase activation by the myristoylated GTP-binding pseudokinase VPS15
Preprint: The class III phosphatidylinositol (PI) 3-kinase complexes I and II (PI3KC3-C1 and -C2) are central to the initiation of macroautophagy and endosomal maturation, respectively. These results provide a pathway of general mechanism for PI3KC3 activation in autophagy and endosome biogenesis and a roadmap for their pharmacological upregulation.
Teams
Themes
Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD
Preprint: The authors’results thus define NAP1 and SINTBAD as cargo receptor rheostats, elevating the threshold for mitophagy initiation by OPTN while promoting the progression of the pathway once set in motion by supporting NDP52. These findings shed light on the cellular strategy to prevent pathway hyperactivity while still ensuring efficient progression.
Teams
Themes
Mitochondrial damage triggers concerted degradation of negative regulators of neuronal autophagy
Preprint: Mutations in genes that regulate mitophagy, a key mitochondrial quality control pathway, are causative for neurological disorders including Parkinson’s. Here, the authors identify a novel stress response pathway activated by mitochondrial damage that regulates mitophagy in neurons.
Teams
Themes
Reconstitution of BNIP3/NIX-mediated autophagy reveals two pathways and hierarchical flexibility of the initiation machinery
During selective autophagy transmembrane, cargo receptors can trigger autophagy by recruiting different complexes and utilizing multiple pathways. This flexibility in autophagy initiation has important therapeutic implications.
Teams
Themes
A unifying model for the role of the ATG8 system in autophagy
Review: The core ATG8 system is one of the most-studied autophagy components. Here, authors reconcile prior observations of the core ATG8 system into a unifying model. Bypass pathways of autophagy that function independently of the core ATG8 system are also discussed.
Teams
Themes
Damaged mitochondria recruit the effector NEMO to activate NF-κB signaling
Published: The connections between molecular mechanisms like mitophagy and tissue-wide features like neuro-inflammation remain unclear. Here, the authors characterize a novel link between these two hallmarks of neurodegeneration.
Teams
Themes
Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation
Published: Here, the authors examine the structural interaction between ATG0A and components of the ULK1 complex to better understand the process of the PINK1- and Parkin- dependent mitophagy pathway implicated in Parkinson’s disease. View original preprint.
Teams
Themes
Unconventional Initiation of PINK1/Parkin Mitophagy by Optineurin
Preprint: Cargo sequestration is a fundamental step of selective autophagy in which cells generate a double membrane structure termed an autophagosome on the surface of cargoes. How OPTN initiates autophagosome formation during selective autophagy remains unknown despite its importance in neurodegeneration. The authors uncover an unconventional path of PINK1/Parkin mitophagy initiation by OPTN.
Teams
Themes
Membrane curvature sensing and stabilization by the autophagic LC3 lipidation machinery
Preprint: During autophagy initiation, the curved phagophore is stabilized. Using in vitro reconstitution, the authors show that WIPI2 and ATG16L1 bind these curved phagophores, WIPI2 binding directs membrane recruitment, and the ATG12-5-16L1 complex is responsible for membrane curvature.
Teams
Themes
In situ structural analysis reveals membrane shape transitions during autophagosome formation
Preprint: A hallmark of PD is the failure of quality control mechanisms in the cell, such as autophagy. The authors combined cell biology with correlative cryo-electron tomography in yeast cells to show a high resolution stepwise structural progression of autophagosome biogenesis. Further, they revealed the organelle interactome for growing autophagosomes.
Themes
Reconstitution of cargo-induced LC3 lipidation in mammalian selective autophagy
Published: Selective autophagy is essential for maintaining cellular homeostasis. Using in vitro reconstitution, the authors explored the details of mitophagy initiation from autophagy receptor engagement through LC3 lipidation. They found that the core machinery engaged during mitophagy depends on different autophagy receptors, but LC3 lipidation is a universal feature. View original preprint.
Teams
Themes
