Distinct sets of lysosomal genes define synucleinopathy and tauopathy
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Neurodegenerative diseases are characterized by distinct proteinaggregates, such as those of α-synuclein and tau. Lysosomaldefect is a key contributor to the accumulation and propagationof aberrant protein aggregates in these diseases. Thediscoveries of common proteinopathies in multiple forms of lysosomalstorage diseases (LSDs) and the identification of someLSD genes as susceptible genes for those proteinopathies suggestcausative links between LSDs and the proteinopathies. Thepresent study hypothesized that defects in lysosomal geneswill differentially affect the propagation of α-synuclein and tauproteins, thereby determining the progression of a specificproteinopathy. We established an imaging-based high-contentsscreening (HCS) system in Caenorhabditis elegans (C. elegans)model, by which the propagation of α-synuclein or tau is measuredby fluorescence intensity. Using this system, we performedRNA interference (RNAi) screening to induce a wide range oflysosomal malfunction through knock down of 79 LSD genes,and to obtain the candidate genes with significant change inprotein propagation. While some LSD genes commonly affectedboth α-synuclein and tau propagation, our study identified thedistinct sets of LSD genes that differentially regulate the propagationof either α-synuclein or tau. The specificity and efficacyof these LSD genes were retained in the disease-relatedphenotypes, such as pharyngeal pumping behavior and life span. This study suggests that distinct lysosomal genes differentiallyregulate the propagation of α-synuclein and tau, and offer asteppingstone to understanding disease specificity.
Abstract
Neurodegenerative diseases are characterized by distinct proteinaggregates, such as those of α-synuclein and tau. Lysosomaldefect is a key contributor to the accumulation and propagationof aberrant protein aggregates in these diseases. Thediscoveries of common proteinopathies in multiple forms of lysosomalstorage diseases (LSDs) and the identification of someLSD genes as susceptible genes for those proteinopathies suggestcausative links between LSDs and the proteinopathies. Thepresent study hypothesized that defects in lysosomal geneswill differentially affect the propagation of α-synuclein and tauproteins, thereby determining the progression of a specificproteinopathy. We established an imaging-based high-contentsscreening (HCS) system in Caenorhabditis elegans (C. elegans)model, by which the propagation of α-synuclein or tau is measuredby fluorescence intensity. Using this system, we performedRNA interference (RNAi) screening to induce a wide range oflysosomal malfunction through knock down of 79 LSD genes,and to obtain the candidate genes with significant change inprotein propagation. While some LSD genes commonly affectedboth α-synuclein and tau propagation, our study identified thedistinct sets of LSD genes that differentially regulate the propagationof either α-synuclein or tau. The specificity and efficacyof these LSD genes were retained in the disease-relatedphenotypes, such as pharyngeal pumping behavior and life span. This study suggests that distinct lysosomal genes differentiallyregulate the propagation of α-synuclein and tau, and offer asteppingstone to understanding disease specificity.
참고문헌 (39)
- Settembre C, "Signals from the lysosome : a control centre for cellular clearance and energy metabolism", Nat Rev Mol Cell Biol, 14, pp.283~296 (2013)
- Lim CY, "The lysosome as a commandand-control center for cellular metabolism", J Cell Biol, 214, pp.653~664 (2016)
- Kroemer G, "Lysosomes and autophagy in cell death control", Nat Rev Cancer, 5, pp.886~897 (2005)
- Ballabio A, "Lysosomal disorders : from storage to cellular damage", Biochim Biophys Acta-Mol Cell Res, 1793, pp.684~696 (2009)
- Oliveira C, "Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease", N Engl J Med, 361, pp.1651~1661 (2009)
- Mata IF, "Glucocerebrosidase gene mutations : a risk factor for Lewy body disorders", Arch Neurol, 65, pp.379~382 (2008)
- Kresojević N, "Mutations in Niemann Pick type C gene are risk factor for Alzheimer’s disease", Med Hypotheses, 83, pp.559~562 (2014)
- Kim DK, "Anti-aging treatments slow propagation of synucleinopathy by restoring lysosomal function", Autophagy, 12, pp.1849~1863 (2016)
- Jadiya P, "A pre-and co-knockdown of RNAseT enzyme, Eri-1, enhances the efficiency of RNAi induced gene silencing in Caenorhabditis elegans", PLoS One, 9, pp.e87635~ (2014)
- IBD Consortium, "Isolation of a novel gene underlying Batten disease", Cell, 82, pp.949~957 (1995)
- Järvelä I, "Biosynthesis and intracellular targeting of the CLN3 protein defective in Batten disease", Hum Mol Genet, 7, pp.85~90 (1998)
- Järvelä I, "Clinical and magnetic resonance imaging findings in batten disease : analysis of the major mutation(1. 02-Kb Deletion)", Ann Neurol, 42, pp.799~802 (1997)
- Kang S, "Altered levels of α-synuclein and sphingolipids in Batten disease lymphoblast cells", Gene, 539, pp.181~185 (2014)
- Nakanishi E, "Impact of Gba2 on neuronopathic Gaucher’s disease and α-synuclein accumulation in medaka(Oryzias latipes)", Mol Brain, 14, pp.1~15 (2021)
- Huebecker M, "Reduced sphingolipid hydrolase activities, substrate accumulation and ganglioside decline in Parkinson’s disease", Mol Neurodegener, 14, pp.1~21 (2019)
- Igisu H, "Progressive accumulation of toxic metabolite in a genetic leukodystrophy", Science, 224, pp.753~755 (1984)
- Chang D, "A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci", Nat Genet, 49, pp.1511~1516 (2017)
- Abdelkarim H, "α-Synuclein interacts directly but reversibly with psychosine : implications for α-synucleinopathies", Sci Rep, 8, pp.1~19 (2018)
- Hatton C, "Prion-like α-synuclein pathology in the brain of infants with Krabbe disease", Brain, 145, pp.1257~1263 (2022)
- Robak LA, "Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease", Brain, 140, pp.3191~3203 (2017)
- Vanier MT, "Type C Niemann-Pick disease : spectrum of phenotypic variation in disruption of intracellular LDL-derived cholesterol processing", Biochim Biophys Acta Mol Basis Dis, 1096, pp.328~337 (1991)
- Auer IA, "Paired helical filament tau(PHFtau)in Niemann-Pick type C disease is similar to PHFtau in Alzheimer’s disease", Acta Neuropathol, 90, pp.547~551 (1995)
- Ohm TG, "Cholesterol and tau protein-findings in Alzheimer’s and Niemann Pick C’s disease", Pharmacopsychiatry, 36, pp.120~126 (2003)
- Sawamura N, "Site-specific phosphorylation of tau accompanied by activation of mitogen-activated protein kinase(MAPK)in brains of Niemann-Pick type C mice", J Cell Biol, 276, pp.10314~10319 (2001)
- Bu B, "Niemann-Pick disease type C yields possible clue for why cerebellar neurons do not form neurofibrillary tangles", Neurobiol Dis, 11, pp.285~297 (2002)
- Saito Y, "Aberrant phosphorylation of α-synuclein in human Niemann-Pick type C1 disease", J Neuropathol, 63, pp.323~328 (2004)
- Myers A, "Susceptibility locus for Alzheimer’s disease on chromosome 10", Science, 290, pp.2304~2305 (2000)
- Von Trotha KT, "Influence of lysosomal acid lipase polymorphisms on chromosome 10 on the risk of Alzheimer’s disease and cholesterol metabolism", Neurosci Lett, 402, pp.262~266 (2006)
- Riemenschneider M, "Association analysis of genes involved in cholesterol metabolism located within the linkage region on chromosome 10 and Alzheimer’s disease", Neurobiol Aging, 25, pp.1305~1308 (2004)
- Papassotiropoulos A, "A cluster of cholesterol-related genes confers susceptibility for Alzheimer’s disease", J Clin Psychiatry, 66, pp.940~ (2005)
- Goedert M, "Assembly of microtubuleassociated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans", Nature, 383, pp.550~553 (1996)
- Kan SH, "Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB", Proc Natl Acad Sci U S A, 111, pp.14870~14875 (2014)
- Litjens T, "Chromosomal localization of ARSB, the gene for human N-acetylgalactosamine-4-sulphatase", Hum Genet, 82, pp.67~68 (1989)
- Vestermark S, "Mental retardation in a patient with Maroteaux-Lamy", Clin Genet, 31, pp.114~117 (1987)
- Schwartz GP, "Hydrocephalus in Maroteaux-Lamy syndrome", Arch Ophthalmol, 116, pp.400~ (1998)
- Vedolin L, "Brain MRI in mucopolysaccharidosis : effect of aging and correlation with biochemical findings", Neurology, 69, pp.917~924 (2007)
- Leverenz JB, "A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology", Brain, 130, pp.1360~1374 (2007)
- Hosokawa M, "Progranulin reduction is associated with increased tau phosphorylation in P301L tau transgenic mice", J Neuropathol, 74, pp.158~165 (2015)
- Murphy KE, "Lysosomal-associated membrane protein 2 isoforms are differentially affected in early Parkinson’s disease", Mov Disord, 30, pp.1639~1647 (2015)