Neurobiol Dis. 2021 Jul;154:105360. doi: 10.1016/j.nbd.2021.105360. Epub 2021 Mar 31.
Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis.
Neurobiology of disease
Jessica Root, Paola Merino, Austin Nuckols, Michelle Johnson, Thomas Kukar
Affiliations
Affiliations
- Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta 30322, Georgia; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta 30322, Georgia.
- Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta 30322, Georgia; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta 30322, Georgia; Department of Neurology, Emory University, School of Medicine, Atlanta 30322, Georgia. Electronic address: [email protected].
PMID: 33812000
PMCID: PMC8113138 DOI: 10.1016/j.nbd.2021.105360
Abstract
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative disorders that are thought to exist on a clinical and pathological spectrum. FTD and ALS are linked by shared genetic causes (e.g. C9orf72 hexanucleotide repeat expansions) and neuropathology, such as inclusions of ubiquitinated, misfolded proteins (e.g. TAR DNA-binding protein 43; TDP-43) in the CNS. Furthermore, some genes that cause FTD or ALS when mutated encode proteins that localize to the lysosome or modulate endosome-lysosome function, including lysosomal fusion, cargo trafficking, lysosomal acidification, autophagy, or TFEB activity. In this review, we summarize evidence that lysosomal dysfunction, caused by genetic mutations (e.g. C9orf72, GRN, MAPT, TMEM106B) or toxic-gain of function (e.g. aggregation of TDP-43 or tau), is an important pathogenic disease mechanism in FTD and ALS. Further studies into the normal function of many of these proteins are required and will help uncover the mechanisms that cause lysosomal dysfunction in FTD and ALS. Mutations or polymorphisms in genes that encode proteins important for endosome-lysosome function also occur in other age-dependent neurodegenerative diseases, including Alzheimer's (e.g. APOE, PSEN1, APP) and Parkinson's (e.g. GBA, LRRK2, ATP13A2) disease. A more complete understanding of the common and unique features of lysosome dysfunction across the spectrum of neurodegeneration will help guide the development of therapies for these devastating diseases.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Keywords: Alzheimer's disease and related dementias (ADRD); Amyotrophic lateral sclerosis (ALS); Autophagy; C9orf72; Frontotemporal dementia (FTD); Frontotemporal lobar degeneration (FTLD); Granulins (GRNs); Lysosome dysfunction; Microtubule-associated protein tau (MAPT); Neurodegeneration; Progranulin (PGRN); Transactive response DNA binding protein 43 kDa (TDP-43); Transcription factor EB (TFEB); Transmembrane protein 106B (TMEM106B); Ubiquitin
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