Endo-lysosomal Dysfunction in Neurodegenerative Diseases: Opinion on Current Progress and Future Direction in the Use of Exosomes As Biomarkers

Overview

Journal Philos Trans R Soc Lond B Biol Sci

Specialty Biology

Date 2024 Feb 18

PMID 38368936

Authors

Mathieu Herman

Grace W Randall

Julia L Spiegel

Delphina J Maldonado

Sabrina Simoes

Affiliations

Soon will be listed here.

Abstract

Over the past two decades, increased research has highlighted the connection between endosomal trafficking defects and neurodegeneration. The endo-lysosomal network is an important, complex cellular system specialized in the transport of proteins, lipids, and other metabolites, essential for cell homeostasis. Disruption of this pathway is linked to a wide range of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and frontotemporal dementia. Furthermore, there is strong evidence that defects in this pathway create opportunities for diagnostic and therapeutic intervention. In this piece, we concisely address the role of endo-lysosomal dysfunction in five neurodegenerative diseases and discuss how future research can investigate this intracellular pathway, including extracellular vesicles with a specific focus on exosomes for the identification of novel disease biomarkers. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.

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References

Hung C, Livesey F . Endolysosome and autophagy dysfunction in Alzheimer disease. Autophagy. 2021; 17(11):3882-3883. PMC: 8632268. DOI: 10.1080/15548627.2021.1963630. View

Antonioni A, Raho E, Lopriore P, Pace A, Latino R, Assogna M . Frontotemporal Dementia, Where Do We Stand? A Narrative Review. Int J Mol Sci. 2023; 24(14). PMC: 10380352. DOI: 10.3390/ijms241411732. View

Danzer K, Kranich L, Ruf W, Cagsal-Getkin O, Winslow A, Zhu L . Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener. 2012; 7:42. PMC: 3483256. DOI: 10.1186/1750-1326-7-42. View

Iguchi Y, Eid L, Parent M, Soucy G, Bareil C, Riku Y . Exosome secretion is a key pathway for clearance of pathological TDP-43. Brain. 2016; 139(Pt 12):3187-3201. PMC: 5840881. DOI: 10.1093/brain/aww237. View

Cataldo A, Peterhoff C, Troncoso J, Gomez-Isla T, Hyman B, Nixon R . Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. Am J Pathol. 2000; 157(1):277-86. PMC: 1850219. DOI: 10.1016/s0002-9440(10)64538-5. View

Sproviero D, La Salvia S, Giannini M, Crippa V, Gagliardi S, Bernuzzi S . Pathological Proteins Are Transported by Extracellular Vesicles of Sporadic Amyotrophic Lateral Sclerosis Patients. Front Neurosci. 2018; 12:487. PMC: 6060258. DOI: 10.3389/fnins.2018.00487. View

Renton A, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs J . A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011; 72(2):257-68. PMC: 3200438. DOI: 10.1016/j.neuron.2011.09.010. View

Iaccarino L, Burnham S, DellAgnello G, Dowsett S, Epelbaum S . Diagnostic Biomarkers of Amyloid and Tau Pathology in Alzheimer's Disease: An Overview of Tests for Clinical Practice in the United States and Europe. J Prev Alzheimers Dis. 2023; 10(3):426-442. DOI: 10.14283/jpad.2023.43. View

Dinkins M, Dasgupta S, Wang G, Zhu G, Bieberich E . Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer's disease. Neurobiol Aging. 2014; 35(8):1792-800. PMC: 4035236. DOI: 10.1016/j.neurobiolaging.2014.02.012. View

10.

Lambert J, Ibrahim-Verbaas C, Harold D, Naj A, Sims R, Bellenguez C . Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013; 45(12):1452-8. PMC: 3896259. DOI: 10.1038/ng.2802. View

11.

Xing H, Tan J, Miao Y, Lv Y, Zhang Q . Crosstalk between exosomes and autophagy: A review of molecular mechanisms and therapies. J Cell Mol Med. 2021; 25(5):2297-2308. PMC: 7933923. DOI: 10.1111/jcmm.16276. View

12.

Ding X, Ma M, Teng J, Teng R, Zhou S, Yin J . Exposure to ALS-FTD-CSF generates TDP-43 aggregates in glioblastoma cells through exosomes and TNTs-like structure. Oncotarget. 2015; 6(27):24178-91. PMC: 4695178. DOI: 10.18632/oncotarget.4680. View

13.

Tanaka Y, Suzuki G, Matsuwaki T, Hosokawa M, Serrano G, Beach T . Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes. Hum Mol Genet. 2017; 26(5):969-988. DOI: 10.1093/hmg/ddx011. View

14.

van Weering J, Scheper W . Endolysosome and Autolysosome Dysfunction in Alzheimer's Disease: Where Intracellular and Extracellular Meet. CNS Drugs. 2019; 33(7):639-648. PMC: 6647502. DOI: 10.1007/s40263-019-00643-1. View

15.

Gao S, Casey A, Sargeant T, Makinen V . Genetic variation within endolysosomal system is associated with late-onset Alzheimer's disease. Brain. 2018; 141(9):2711-2720. DOI: 10.1093/brain/awy197. View

16.

Boman A, Svensson S, Boxer A, Rojas J, Seeley W, Karydas A . Distinct Lysosomal Network Protein Profiles in Parkinsonian Syndrome Cerebrospinal Fluid. J Parkinsons Dis. 2016; 6(2):307-15. PMC: 4927933. DOI: 10.3233/JPD-150759. View

17.

Rani K, Rastogi S, Vishwakarma P, Bharti P, Sharma V, Renu K . A novel approach to correlate the salivary exosomes and their protein cargo in the progression of cognitive impairment into Alzheimer's disease. J Neurosci Methods. 2020; 347:108980. DOI: 10.1016/j.jneumeth.2020.108980. View

18.

Alvarez-Erviti L, Seow Y, Schapira A, Gardiner C, Sargent I, Wood M . Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol Dis. 2011; 42(3):360-7. PMC: 3107939. DOI: 10.1016/j.nbd.2011.01.029. View

19.

Szabo M, Mishra S, Knupp A, Young J . The role of Alzheimer's disease risk genes in endolysosomal pathways. Neurobiol Dis. 2021; 162:105576. PMC: 9071255. DOI: 10.1016/j.nbd.2021.105576. View

20.

Rastogi S, Sharma V, Bharti P, Rani K, Modi G, Nikolajeff F . The Evolving Landscape of Exosomes in Neurodegenerative Diseases: Exosomes Characteristics and a Promising Role in Early Diagnosis. Int J Mol Sci. 2021; 22(1). PMC: 7795439. DOI: 10.3390/ijms22010440. View