Output 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.
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Regulation of the proteasome 20S core particle by the Parkinsonism-associated Proteins FBXO7 and PI31
Genetic forms of PD are associated with variants in FBXO7 and PI31. Combining biochemical and structural approaches, we describe the proteasome interaction of these proteins and map disease variants to disruption of proteasome interaction.
Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress
Cryo-ET showed protein aggregates, altered cristae, and reduced ribosome complexes in stressed mitochondria. Mitochondrial Hsp60 undergoes conformational changes to aid in protein folding, shedding light on mitochondrial proteostasis mechanisms.
Mechanisms Controlling Selective Elimination of Damaged Lysosomes
Lysophagy, triggered by membrane rupture, involves galectins binding to lysosomal contents to promote autophagic recycling. Damaged lysosomes are ubiquitylated, leading to autophagosome formation for degradation in healthy lysosomes.
In situ structural analysis reveals membrane shape transitions during autophagosome formation
The authors combined cell biology with correlative cryo-electron tomography in yeast cells to show a high resolution stepwise structural progression of autophagosome biogenesis.
Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis.
Homozygous mutations of granulin precursor (GRN) lead to neuronal ceroid lipofuscinosis1, a severe neurodevelopmental disease, in humans and neuroinflammation in mice2. Haploinsufficiency of GRN almost invariably causes frontotemporal dementia…
Quantitative proteomics reveals the selectivity of ubiquitin-binding autophagy receptors in the turnover of damaged lysosomes by lysophagy
The authors used proteomics to develop a quantitative snapshot of the proteins involved in lysophagy. Among the proteins identified, they found that TAX1BP1 and TBK1 are both required for lysophagy.
Mechanisms underlying ubiquitin-driven selective mitochondrial and bacterial autophagy
The authors review efforts to understand the biochemical mechanisms and principles by which cargo are marked with ubiquitin and how ubiquitin-binding cargo receptors use conserved structural modules to recruit autophagosome initiation machinery
PARK15/FBXO7 is dispensable for PINK1/Parkin mitophagy in iNeurons and HeLa cell systems
PINK1 and Parkin promote damaged mitochondria removal through Ub phosphorylation, Parkin activation. FBXO7 mutation in PD may not affect mitophagy in HeLa and neuron cells, suggesting it may not play a significant role in Parkin-dependent mitophagy.
The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends
Using microfluidic diffusional sizing, the authors show that the molecular chaperone family Hsp70 (specifically Hsc70, DnaJB, and Apg2) can completely dissolve alpha-synuclein aggregation and revert it back to its monomeric state.
Spatial snapshots of amyloid precursor protein intramembrane processing via early endosome proteomics
The authors developed an assay, Endo-IP, to rapidly isolate early and sorting endosomes. Using this method, they found a unique proteomic landscape of early/sorting endosomes, distinct from lysosomal proteomic landscape.
Quantitative mapping of autophagic cargo during nutrient stress reveals YIPF3-YIPF4 as membrane receptors for Golgiphagy
Macroautophagy degrades cellular macromolecules during nutrient stress, providing building blocks and remodeling the proteome. YIPF3 and YIPF4 are identified as receptors for Golgiphagy, crucial for eliminating Golgi membrane proteins.
In situ architecture of neuronal α-Synuclein inclusions
Alpha-synuclein aggregation has been associated with Parkinson’s disease. Using cutting-edge imaging tools, the authors show neuronal alpha-synuclein inclusions within their native states.
The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model
Tau neuronal aggregation is a driver of some neurodegenerative disorders. The authors show that a protein,Clusterin, delays Tau aggregation and suppresses seeding activity.
Proteostasis and lysosomal quality control deficits in Alzheimer’s disease neurons
Lysosomal quality control (LQC) pathways are notably impaired in both aging and AD, leading to neuronal vulnerability and cytotoxicity. Neurons show amyloid-β inclusions, and enhancing lysosomal function can help alleviate AD-related pathologies.
The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system
Protein aggregates, like tau, are associated with neurodegenerative diseases. The authors show that the AAA+ chaperone, VCP, is recruited to ubiquitylated Tau, resulting in disaggregation.
