{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:16:18Z","timestamp":1790946978940,"version":"4.1.0"},"reference-count":109,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Neurodegenerative diseases, including Alzheimer\u2019s disease and Parkinson\u2019s disease, are characterized by progressive neuronal loss, leading to cognitive and motor impairments. Although these diseases have distinct clinical manifestations, they share pathological hallmarks such as protein aggregation and lysosomal dysfunction. The lysosome plays a vital role in maintaining cellular homeostasis by mediating the degradation and recycling of proteins, lipids, and other macromolecules. As such, it serves as a central hub for both proteostasis and lipostasis. This review outlines genetic and mechanistic parallels between rare lysosomal lipid storage diseases, such as Gaucher disease and Niemann\u2013Pick disease, and more prevalent neurodegenerative diseases. We discuss how impaired lysosomal sphingolipid metabolism compromises lysosomal integrity, disrupts proteostasis, and contributes to neurodegeneration. Furthermore, we describe how age-related decline in lysosomal function may similarly drive neurodegeneration in the absence of overt genetic mutations. Taken together, this review highlights the lysosome as a central integrator of protein and lipid homeostasis and emphasizes the bidirectional relationship between lipostasis and proteostasis, whereby disruption of one adversely affects the other in the pathogenesis of multiple neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/cells14110845","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T11:14:12Z","timestamp":1749035652000},"page":"845","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8202-3702","authenticated-orcid":false,"given":"Jessica","family":"Tittelmeier","sequence":"first","affiliation":[{"name":"Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians University of Munich (LMU Munich), Pettenkoferstrasse 11, 80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8689-1363","authenticated-orcid":false,"given":"Carmen","family":"Nussbaum-Krammer","sequence":"additional","affiliation":[{"name":"Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians University of Munich (LMU Munich), Pettenkoferstrasse 11, 80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/ncb1901","article-title":"Transmission and spreading of tauopathy in transgenic mouse brain","volume":"11","author":"Clavaguera","year":"2009","journal-title":"Nat. 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