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For over a century, researchers have observed similar neurodegenerative hallmarks in brains of people affected by rare early-onset lysosomal storage diseases and late-onset neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Increasing evidence suggests these apparently disparate diseases share a common underlying feature, namely, a dysfunctional clearance of cellular cargo through the secretory-endosomal-autophagic-lysosomal-exocytic (SEALE) network. By providing examples of rare and common neurodegenerative diseases known to have pathologically altered cargo flux through the SEALE network, we explore the unifying hypothesis that impaired catabolism or exocytosis of SEALE cargo, places a burden of stress on neurons that initiates pathogenesis. We also describe how a growing understanding of genetic, epigenetic and age-related modifications of the SEALE network, has inspired a number of novel disease-modifying therapeutic approaches aimed at alleviating SEALE storage and providing therapeutic benefit to people affected by these devastating diseases across the age spectrum.

Original publication

DOI

10.1016/j.beem.2014.08.009

Type

Journal article

Journal

Best Pract Res Clin Endocrinol Metab

Publication Date

03/2015

Volume

29

Pages

127 - 143

Keywords

Alzheimer's disease, Niemann Pick disease, amyloid, autophagy, endosome, exocytosis, glycosphingolipid, lysosomal storage disease, lysosome, neurodegeneration, Age Factors, Alzheimer Disease, Autophagy, Brain, Endosomes, Exocytosis, Humans, Lysosomal Storage Diseases, Lysosomes, Neurodegenerative Diseases, Parkinson Disease