Cell-type resolved protein atlas of brain lysosomes identifies SLC45A1-associated disease as a lysosomal disorder
Mutations in lysosomal genes cause neurodegeneration and neuronopathic 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 lysosomes from mouse neurons, astrocytes, oligodendrocytes, and microglia. We identify dozens of proteins not previously annotated as lysosomal and reveal the diversity of lysosomal composition across brain cell types. Notably, we identified SLC45A1, a gene whose mutations cause a monogenic neurological disease, as a neuron-specific lysosomal protein. Loss of SLC45A1 causes lysosomal dysfunction in vitro and in vivo. SLC45A1 functions as a lysosomal sugar transporter and impacts the stability of the V1 subunits of the vacuolar ATPase (V-ATPase). Consistently, SLC45A1 loss reduces lysosomal V1 subunits, elevates lysosomal pH, and disrupts iron homeostasis, causing mitochondrial dysfunction. Altogether, our work redefines SLC45A1-associated disease as an LSD and establishes a comprehensive map to study lysosome biology at cell-type resolution.
Authors
- Ali Ghoochani (ORCID: https://orcid.org/0000-0002-5352-0072)
- Christian Franke (ORCID: https://orcid.org/0000-0002-0326-7232)
- Marc Gastou (ORCID: https://orcid.org/0000-0003-3030-4809)
- Eshaan S. Rawat (ORCID: https://orcid.org/0000-0002-2595-7605)
- Uche N. Medoh (ORCID: https://orcid.org/0000-0002-7670-4093)
- Julia C. Heiby (ORCID: https://orcid.org/0000-0001-8191-8945)
- Kwamina Nyame (ORCID: https://orcid.org/0000-0001-8898-4689)
- Christina Valkova
- Nouf N. Laqtom (ORCID: https://orcid.org/0000-0002-0167-2656)
- Domenico Di Fraia (ORCID: https://orcid.org/0000-0003-4270-8464)
- Christoph Kaether (ORCID: https://orcid.org/0000-0002-6874-2276)
- William Durso (ORCID: https://orcid.org/0000-0003-4618-4856)
- Marius Wernig (ORCID: https://orcid.org/0000-0002-5309-515X)
- Abu-Remaileh Monther
- Alessandro Ori
- Mohit Rastogi
- Alina Isakova
- Vincent Hernandez
- Wentao Dong
Institutions
- Neurosciences Institute (US)
- Cardiovascular Institute of the South (US)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Friedrich Schiller University Jena (DE)
- Stanford University (US)
Publication Details
- Journal
- Cell
- Published
- 2026-01-22
- DOI
- https://doi.org/10.1016/j.cell.2025.12.012
- Citations
- 1
- Primary Topic
- Lysosomal Storage Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 32.84