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Neurobiol Dis. 2019 Feb;122:94-105. doi: 10.1016/j.nbd.2018.05.015. Epub 2018 May 30.

Lysosome trafficking and signaling in health and neurodegenerative diseases.

Author information

1
Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Psychiatry, New York University Langone Medical Center, New York, NY 10016, USA. Electronic address: plie@nki.rfmh.org.
2
Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Psychiatry, New York University Langone Medical Center, New York, NY 10016, USA; Department of Cell Biology, New York University Langone Medical Center, New York, NY 10016, USA; NYU Neuroscience Institute, New York University Langone Medical Center, New York, NY 10016, USA.

Abstract

Lysosomes, single-membrane organelles defined by a uniquely strong acidic lumenal pH and high content of acid hydrolases, are the shared degradative compartments of the endocytic and autophagic pathways. These pathways, and especially lysosomes, are points of particular vulnerability in many neurodegenerative diseases. Beyond the role of lysosomes in substrate degradation, new findings have ascribed to lysosomes the leading role in sensing and responding to cellular nutrients, growth factors and cellular stress. This review aims to integrate recent concepts of basic lysosome biology and pathobiology as a basis for understanding neurodegenerative disease pathogenesis. Here, we discuss the newly recognized signaling functions of lysosomes and specific aspects of lysosome biology in neurons while re-visiting the classical defining criteria for lysosomes and the importance of preserving strict definitions. Our discussion emphasizes dynein-mediated axonal transport of maturing degradative organelles, with further consideration of their roles in synaptic function. We finally examine how distinctive underlying disturbances of lysosomes in various neurodegenerative diseases result in unique patterns of auto/endolysosomal mistrafficking. The rapidly emerging understanding of lysosomal trafficking and disruptions in lysosome signaling is providing valuable clues to new targets for disease-modifying therapies.

KEYWORDS:

Autophagy; Axonal transport; Dynein; Lysosomal signaling; Lysosome; Lysosome positioning; Neurodegenerative disease; Nutrient-sensing

PMID:
29859318
PMCID:
PMC6381838
DOI:
10.1016/j.nbd.2018.05.015
[Indexed for MEDLINE]
Free PMC Article

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