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PLOS ONE  2012 

Disruption of the Autophagy-Lysosome Pathway Is Involved in Neuropathology of the nclf Mouse Model of Neuronal Ceroid Lipofuscinosis

DOI: 10.1371/journal.pone.0035493

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Abstract:

Variant late-infantile neuronal ceroid lipofuscinosis, a fatal lysosomal storage disorder accompanied by regional atrophy and pronounced neuron loss in the brain, is caused by mutations in the CLN6 gene. CLN6 is a non-glycosylated endoplasmic reticulum (ER)-resident membrane protein of unknown function. To investigate mechanisms contributing to neurodegeneration in CLN6 disease we examined the nclf mouse, a naturally occurring model of the human CLN6 disease. Prominent autofluorescent and electron-dense lysosomal storage material was found in cerebellar Purkinje cells, thalamus, hippocampus, olfactory bulb and in cortical layer II to V. Another prominent early feature of nclf pathogenesis was the localized astrocytosis that was evident in many brain regions and the more widespread microgliosis. Expression analysis of mutant Cln6 found in nclf mice demonstrated synthesis of a truncated protein with a reduced half-life. Whereas the rapid degradation of the mutant Cln6 protein can be inhibited by proteasomal inhibitors, there was no evidence for ER stress or activation of the unfolded protein response in various brain areas during postnatal development. Age-dependent increases in LC3-II, ubiquitinated proteins, and neuronal p62-positive aggregates were observed, indicating a disruption of the autophagy-lysosome degradation pathway of proteins in brains of nclf mice, most likely due to defective fusion between autophagosomes and lysosomes. These data suggest that proteasomal degradation of mutant Cln6 is sufficient to prevent the accumulation of misfolded Cln6 protein, whereas lysosomal dysfunction impairs constitutive autophagy promoting neurodegeneration.

References

[1]  Jalanko A, Braulke T (2009) Neuronal ceroid lipofuscinoses. Biochim Biophys Acta 1793: 697–709.
[2]  Noskova L, Stranecky V, Hartmannova H, Pristoupilova A, Baresova V, et al. (2011) Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. Am J Hum Genet 89: 241–252.
[3]  Mole SE, Williams RE, Goebel HH (2005) Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics 6: 107–126.
[4]  Goebel HH, Wisniewski KE (2004) Current state of clinical and morphological features in human NCL. Brain Pathol 14: 61–69.
[5]  Mitchison HM, Lim MJ, Cooper JD (2004) Selectivity and types of cell death in the neuronal ceroid lipofuscinoses. Brain Pathol 14: 86–96.
[6]  Heine C, Koch B, Storch S, Kohlschütter A, Palmer DN, et al. (2004) Defective endoplasmic reticulum-resident membrane protein CLN6 affects lysosomal degradation of endocytosed arylsulfatase A. J Biol Chem 279: 22347–22352.
[7]  Mole SE, Michaux G, Codlin S, Wheeler RB, Sharp JD, et al. (2004) CLN6, which is associated with a lysosomal storage disease, is an endoplasmic reticulum protein. Exp Cell Res 298: 399–406.
[8]  Gao H, Boustany RM, Espinola JA, Cotman SL, Srinidhi L, et al. (2002) Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. Am J Hum Genet 70: 324–335.
[9]  Wheeler RB, Sharp JD, Schultz RA, Joslin JM, Williams RE, et al. (2002) The gene mutated in variant late-infantile neuronal ceroid lipofuscinosis (CLN6) and in nclf mutant mice encodes a novel predicted transmembrane protein. Am J Hum Genet 70: 537–542.
[10]  Thelen M, Fehr S, Schweizer M, Braulke T, Galliciotti G (2011) High expression of disease-related Cln6 in the cerebral cortex, purkinje cells, dentate gyrus, and hippocampal ca1 neurons. J Neurosci Res 90: 568–574.
[11]  Arsov T, Smith KR, Damiano J, Franceschetti S, Canafoglia L, et al. (2011) Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6. Am J Hum Genet 88: 566–573.
[12]  Kurze AK, Galliciotti G, Heine C, Mole SE, Quitsch A, et al. (2010) Pathogenic mutations cause rapid degradation of lysosomal storage disease-related membrane protein CLN6. Hum Mutat 31: E1163–1174.
[13]  Bronson RT, Donahue LR, Johnson KR, Tanner A, Lane PW, et al. (1998) Neuronal ceroid lipofuscinosis (nclf), a new disorder of the mouse linked to chromosome 9. Am J Med Genet 77: 289–297.
[14]  Oswald MJ, Palmer DN, Kay GW, Shemilt SJ, Rezaie P, et al. (2005) Glial activation spreads from specific cerebral foci and precedes neurodegeneration in presymptomatic ovine neuronal ceroid lipofuscinosis (CLN6). Neurobiol Dis 20: 49–63.
[15]  Pressey SN, O'Donnell KJ, Stauber T, Fuhrmann JC, Tyynel? J, et al. (2010) Distinct neuropathologic phenotypes after disrupting the chloride transport proteins ClC-6 or ClC-7/Ostm1. J Neuropathol Exp Neurol 69: 1228–1246.
[16]  Palmer DN, Barns G, Husbands DR, Jolly RD (1986) Ceroid lipofuscinosis in sheep. II. The major component of the lipopigment in liver, kidney, pancreas, and brain is low molecular weight protein. J Biol Chem 261: 1773–1777.
[17]  Jabs S, Quitsch A, Kakela R, Koch B, Tyynel? J, et al. (2008) Accumulation of bis(monoacylglycero)phosphate and gangliosides in mouse models of neuronal ceroid lipofuscinosis. J Neurochem 106: 1415–1425.
[18]  Cooper JD, Russell C, Mitchison HM (2006) Progress towards understanding disease mechanisms in small vertebrate models of neuronal ceroid lipofuscinosis. Biochim Biophys Acta 1762: 873–889.
[19]  Kay GW, Palmer DN, Rezaie P, Cooper JD (2006) Activation of non-neuronal cells within the prenatal developing brain of sheep with neuronal ceroid lipofuscinosis. Brain Pathol 16: 110–116.
[20]  Oswald MJ, Palmer DN, Kay GW, Barwell KJ, Cooper JD (2008) Location and connectivity determine GABAergic interneuron survival in the brains of South Hampshire sheep with CLN6 neuronal ceroid lipofuscinosis. Neurobiol Dis 32: 50–65.
[21]  Wei H, Kim SJ, Zhang Z, Tsai PC, Wisniewski KE, et al. (2008) ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones. Hum Mol Genet 17: 469–477.
[22]  Zhang Z, Lee YC, Kim SJ, Choi MS, Tsai PC, et al. (2006) Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL. Hum Mol Genet 15: 337–346.
[23]  Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8: 519–529.
[24]  Lindholm D, Wootz H, Korhonen L (2006) ER stress and neurodegenerative diseases. Cell Death Differ 13: 385–392.
[25]  Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451: 1069–1075.
[26]  Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, et al. (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441: 880–884.
[27]  Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, et al. (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441: 885–889.
[28]  Koike M, Shibata M, Waguri S, Yoshimura K, Tanida I, et al. (2005) Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease). Am J Pathol 167: 1713–1728.
[29]  Cao Y, Espinola JA, Fossale E, Massey AC, Cuervo AM, et al. (2006) Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. J Biol Chem 281: 20483–20493.
[30]  Rubinsztein DC (2006) The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443: 780–786.
[31]  Kielar C, Maddox L, Bible E, Pontikis CC, Macauley SL, et al. (2007) Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis 25: 150–162.
[32]  Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, et al. (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282: 24131–24145.
[33]  Ni M, Lee AS (2007) ER chaperones in mammalian development and human diseases. FEBS Lett 581: 3641–3651.
[34]  Farfel-Becker T, Vitner E, Dekel H, Leshem N, Enquist IB, et al. (2009) No evidence for activation of the unfolded protein response in neuronopathic models of Gaucher disease. Hum Mol Genet 18: 1482–1488.
[35]  Nakatsukasa K, Huyer G, Michaelis S, Brodsky JL (2008) Dissecting the ER-associated degradation of a misfolded polytopic membrane protein. Cell 132: 101–112.
[36]  Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132: 27–42.
[37]  Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, et al. (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19: 5720–5728.
[38]  Settembre C, Fraldi A, Jahreiss L, Spampanato C, Venturi C, et al. (2008) A block of autophagy in lysosomal storage disorders. Hum Mol Genet 17: 119–129.
[39]  Kiselyov K, Jennigs JJ , Rbaibi Y, Chu CT (2007) Autophagy, mitochondria and cell death in lysosomal storage diseases. Autophagy 3: 259–262.
[40]  Nedelsky NB, Todd PK, Taylor JP (2008) Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection. Biochim Biophys Acta 1782: 691–699.
[41]  Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278: 25009–25013.
[42]  Kamimoto T, Shoji S, Hidvegi T, Mizushima N, Umebayashi K, et al. (2006) Intracellular inclusions containing mutant alpha1-antitrypsin Z are propagated in the absence of autophagic activity. J Biol Chem 281: 4467–4476.
[43]  Pontikis CC, Cella CV, Parihar N, Lim MJ, Chakrabarti S, et al. (2004) Late onset neurodegeneration in the Cln3-/- mouse model of juvenile neuronal ceroid lipofuscinosis is preceded by low level glial activation. Brain Res 1023: 231–242.
[44]  Pontikis CC, Cotman SL, MacDonald ME, Cooper JD (2005) Thalamocortical neuron loss and localized astrocytosis in the Cln3Deltaex7/8 knock-in mouse model of Batten disease. Neurobiol Dis 20: 823–836.
[45]  Cooper JD (2010) The neuronal ceroid lipofuscinoses: the same, but different? Biochem Soc Trans 38: 1448–1452.
[46]  Waheed A, Gottschalk S, Hille A, Krentler C, Pohlmann R, et al. (1988) Human lysosomal phosphatase is transported as a transmembrane protein in transfected baby hamster kidney cells. EMBO J 7: 2351–2358.
[47]  Heine C, Quitsch A, Storch S, Martin Y, Lonka L, et al. (2007) Topology and endoplasmic reticulum retention signals of the lysosomal storage disease-related membrane protein CLN6. Mol Membr Biol 24: 74–87.
[48]  Yla-Anttila P, Vihinen H, Jokitalo E, Eskelinen EL (2009) Monitoring autophagy by electron microscopy in mammalian cells. Methods Enzymol 452: 143–164.
[49]  Bible E, Gupta P, Hofmann SL, Cooper JD (2004) Regional and cellular neuropathology in the palmitoyl protein thioesterase-1 null mutant mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis 16: 346–359.
[50]  Damme M, Stroobants S, Walkley SU, Lüllmann-Rauch R, D'Hooge R, et al. (2011) Cerebellar alterations and gait defects as therapeutic outcome measures for enzyme replacement therapy in alpha-mannosidosis. J Neuropathol Exp Neurol 70: 83–94.

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