Cell-Type Resolved Protein Atlas of Brain Lysosomes Identifies SLC45A1-Associated Disease as a Lysosomal Disorder.

Autor:	Ghoochani A; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.; Department of Genetics, Stanford University, Stanford, CA 94305, USA.; The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA 94305, USA.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network; Chevy Chase, MD, 20815, USA.; These authors contributed equally., Heiby JC; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.; Department of Genetics, Stanford University, Stanford, CA 94305, USA.; The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA 94305, USA.; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) e.V., Jena, Germany.; These authors contributed equally., Rawat ES; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.; Department of Genetics, Stanford University, Stanford, CA 94305, USA.; The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA 94305, USA.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network; Chevy Chase, MD, 20815, USA., Medoh UN; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.; Department of Genetics, Stanford University, Stanford, CA 94305, USA.; The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA 94305, USA.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network; Chevy Chase, MD, 20815, USA.; Current affiliation: Arc Institute, Palo Alto, CA 94304, USA., Di Fraia D; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) e.V., Jena, Germany.; Current affiliation: Department of Biology, University of Rochester, Rochester, NY, USA., Dong W; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.; Department of Genetics, Stanford University, Stanford, CA 94305, USA.; The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA 94305, USA.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network; Chevy Chase, MD, 20815, USA., Gastou M; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA., Nyame K; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.; Department of Genetics, Stanford University, Stanford, CA 94305, USA.; The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA 94305, USA.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network; Chevy Chase, MD, 20815, USA., Laqtom NN; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.; Department of Genetics, Stanford University, Stanford, CA 94305, USA.; The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA 94305, USA.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network; Chevy Chase, MD, 20815, USA., Gomez-Ospina N; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA., Ori A; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) e.V., Jena, Germany.; Co-senior authors., Abu-Remaileh M; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.; Department of Genetics, Stanford University, Stanford, CA 94305, USA.; The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA 94305, USA.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network; Chevy Chase, MD, 20815, USA.; The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA.; Co-senior authors.; Lead author.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 14. Date of Electronic Publication: 2024 Oct 14.
DOI:	10.1101/2024.10.14.618295
Abstrakt:	Mutations in lysosomal genes cause neurodegeneration and neurological lysosomal storage disorders (LSDs). Despite their essential role in brain homeostasis, the cell-type-specific composition and function of lysosomes remain poorly understood. Here, we report a quantitative protein atlas of the lysosome from mouse neurons, astrocytes, oligodendrocytes, and microglia. We identify dozens of novel lysosomal proteins and reveal the diversity of the lysosomal composition across brain cell types. Notably, we discovered SLC45A1, mutations in which cause a monogenic neurological disease, as a neuron-specific lysosomal protein. Loss of SLC45A1 causes lysosomal dysfunction in vitro and in vivo. Mechanistically, SLC45A1 plays a dual role in lysosomal sugar transport and stabilization of V1 subunits of the V-ATPase. SLC45A1 deficiency depletes the V1 subunits, elevates lysosomal pH, and disrupts iron homeostasis causing mitochondrial dysfunction. Altogether, our work redefines SLC45A1-associated disease as a LSD and establishes a comprehensive map to study lysosome biology at cell-type resolution in the brain and its implications for neurodegeneration. Competing Interests: Declaration of interest M.A-R. is a scientific advisory board member of Lycia Therapeutics and advisor for Scenic Biotech. All other authors declare no competing interests.
Databáze:	MEDLINE
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