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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.
Article
RAB3 phosphorylation by pathogenic LRRK2 impairs trafficking of synaptic vesicle precursors
Published: Gain-of-function mutations in the LRRK2 gene cause Parkinson’s disease (PD), characterized by debilitating motor and non-motor symptoms. The authors’ results reveal a mechanism by which pathogenic hyperactive LRRK2 may contribute to the altered synaptic homeostasis associated with characteristic non-motor and cognitive manifestations of PD. View original preprint.
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Three-step docking by WIPI2, ATG16L1, and ATG3 delivers LC3 to the phagophore
In a near-complete pathway from the initial membrane recruitment to the LC3 lipidation reaction, the three-step targeting of the ATG12–ATG5-ATG16L1 machinery establishes a high level of regulatory control.
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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.
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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.
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A RAB7A phosphoswitch coordinates rubicon homology protein regulation of PINK1/Parkin-dependent mitophagy
Preprint: 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.
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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.
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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.
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Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex
The presence of PI3KC3-C1 induces a rearrangement of ULK1C from a FIP200:ATG13:ULK1 2:1:1 to a 2:2:2 stoichiometry by dislocating an ATG13 loop from an inhibitory site on the dimeric FIP200 scaffold. This suggests a mechanism for the initiation of autophagy through PI3KC3-C1-induced dimerization of ULK1 as bound to FIP200, followed by an activating trans-autophosphorylation of ULK1.
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Article
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.
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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.
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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.
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Structural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy
Published: Autophagy is a conserved mechanism for the sequestration and degradation of cytosolic cargo. ATG16L1 and WIPI2 are essential for autophagy initiation. The authors showed through structural determination how ATG16L1 and WIPI2 interact and compared the other WIPI proteins showing the variety of mechanisms of membrane recruitment by WIPI proteins. View original preprint.
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ALS- and FTD-associated missense mutations in TBK1 differentially disrupt mitophagy
Published: TBK1 mutations are linked to neurodegenerative disorders. The authors explored how TBK1 functions in PINK1/Parkin-dependent mitophagy and how mutations lead to disease. TBK1 recruitment and kinase activity contributed to the clearance of damaged mitochondria (mitophagy). Further, they showed that TBK1 presence alone could disrupt the mitochondrial network. View original preprint.
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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.
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