Ubiquitin, Lysosomes, and Neurodegenerative Diseasesa R. JOHN MAYE&&LAJOS LASZLO,& MICHAEL LANDON,’ JAMES HOPE: AND JAMES LOWE Departmmn af ‘Biochemiw and cPatbolom University of Notiingham Medical School @en 3 Medual Centre Notringbarn NG7 2UH1 United Kingdom and dAFRC/MRC Neuropathgenis Unit Ogston Building King’s Building Site West Mains Rcud Eainbutyh EH9 3JF, Scotland

INTRODUCTION There are several issues which need to be addressed concerning ubiquitin, lysosomes and neurodegenerative diseases. The first is a brief description of how the initial observations by immunohistochemistry of some form of ubiquitin-protein deposit in cells have been extended to identify a family of ubiquitin-filamentdegenerative diseases. This family includes Alzheimer’s disease, diffuse Lewy body disease (or the Lewy variant of Alzheimer’s disease), Parkinson’s disease and amyotrophic lateral sclerosis (motor neurone disease) as well as some cerebellar astrocytomas and alcoholic liver disease.l Immunohistochemical observations have also shown that some form of ubiquitinprotein deposit occurs as structures adjacent to amyloid plaques in idiopathic neurodegenerative diseases (e.g., Alzheimer’s disease and Lewy body disease) and in transmissible neurodegenerative diseases (prion encephalopathies such as scrapie and CreutzfeldtJakob disease). Coarser structures, containing ubiquitin-protein conjugates, can also appear intraneuronally (as granulovacuolar degeneration in hippocampal neurones in Alzheimer’s disease) and adjacent to neurones (in scrapie-infected mouse brain). Fine dot-like deposits can be seen throughout the neuropil in normal human aging as well as in the neurodegenerative diseases. These dot-like structures are lysosome-related dense, multivesicular o r multilamellar b o d i e ~ . ~ - ~ Ubiquitin-protein deposits can be observed by immunogold electron microscopy in hnctionally compromised lysosomes6 as well as in normal lysosomes (e.g., in fibroblasts and polymorphonuclear n e u t r ~ p h i l s ~and . ~ ) in lysosomes of cells infected with a virus (Epstein-Barr virus).’ Cells with a temperature-sensitive mutation in the activation of ubiquitin for protein-conjugation fail to load ubiquitin-protein conjugates into lysosomes at the nonpermissive temperature. l o Protein ubiquitination therefore appears ‘We would like to thank the Agricultural and Food Research Council, the Motor Neurone Disease Association, and the Parkinson’s Disease Society of Great Britain for support of this work. 149

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to have a dual role in intracellular protein degradation, the well known role in ATPdependent nonlysosomal protein catabolism and a much less well characterized function in lysosomal protein degradation. Finally, recent immunogold electron microscopical studies have shown that lysosome-related bodies, identified by the presence of ubiquitin-protein conjugates, a heatshock protein 70 and lysosomal P-glucuronidase are central to the prion encephalopathies. l2 Pleiomorphic multivesicular and tubulovesicular bodies containing the markers are found throughout the neuropil, where they presumably correspond to the previously observed ubiquitin-positive dot-like structures. l3 Multivesicular bodies also occur in axosomatic processes, which presumably correspond to the coarser structures initially seen immunohistochemically adjacent to nerve cell b o d i e ~ . ~ Lysosomal involvement in both the idiopathic and transmissible neurodegenerative diseases offers attractive new mechanisms for events which cannot otherwise be explained satisfactorily. Lysosome-relatedorganelles may offer the only intracellular compartment in which to generate and eject the amyloidogeneic fragments of the amyloid precursor protein in Alzheimer-relateddisorders and in which to generate the abnormal isoform of the PrP protein in the prion encephalopathies. Plausible models to account for these statements will be considered.

Ubiquitin-FilamentDisorders Ubiquitinprotein deposits were first demonstrated immunohistochemically in association with neurofibrillary tangles in Alzheimer's disease.lc16 The reason for the occurrence of such deposits is unknown, although some impairment or malfunction of the nonlysosomal ubiquitin-dependent proteolytic system has been suggested. A full explanation for the deposits will not be forthcoming until the roles of protein ubiquitination in all intracellular protein catabolic systems are better understood. Neurofibrillary tangles are based on paired helical filaments which are now known to contain abnormally phosphorylated forms of the microtubule-associated protein, tau." Other components of the tangles are less well defined, for example, it is still contentious if tangles contain any neurofilaments. Neurofilaments are one of the family of intermediate filaments which are the element of the cytoskeleton most sensitive to a variety of stresses, including heat-shock, poisons, radiation, etc.'" Intermediate filaments show reversible collapse around the cell nucleus in response to such deleterious stimuli. The same response occurs during the internalization of viral membrane proteins from the plasma membrane for eventual lysosomal degradation or ejection from the cell.'" In cells producing large quantities of a single viral membrane protein irreversible collapse of intermediate filaments to form inclusions can occur. l9 In chronic degenerative diseases inclusions, to which intermediate filaments definitively contribute, also contain ubiquitin-protein conjugates. Such inclusions include the neurofilament-containingLRwy bodies in Lewy body dementia,2 the glial filamentcontaining Rosenthal fibres in cerebellar astrocytomas,20the cytokeratin-containing Mallory bodies in alcoholic liver disease and the desmin-containing cytoplasmic inclusions in a cytoplasmic body rny0pathy.l Ubiquitin-protein deposits are also a feature of filamentous inclusions of unknown origin first seen by ubiquitin immunocytochemistry in amyotrophic lateral sclerosis (motor neurone disease).20.21 Ubiquitin immunocytochemistry has not only been important in unravelling commonalities in ostensibly unrelated diseases but also in diagnosis. The true incidence of cortical Lewy bodies was only appreciated through staining for ubiquitin-protein conjugate^^^-^^ where the technique has revealed that 25-33% of all the cases of dementia coming to brain autopsy possess large numbers these bodies. Diffuse Lewy

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body disease, with cortical Lmvy bodies as well as extracellular amyloid plaques, is, therefore, the second most common cause of dementia after Alzheimer’s disease (which accounts for approximately 50% of cases).

Ubiquitinand the Lysosome System Protein ubiquitination has been extensively studied in ATPdependent nonlysosomal proteolysi~,~~ but the idea that ubiquitin might have any role in lysosome function was not considered. One of the first indications that ubiquitin could be involved in lysosome function came from the observation that ubiquitin-protein conjugates were enriched in areas of granulovacuolar degeneration in hippocampal neurones in Alzheimer’s disease.2As the name suggests, conventional histochemistry shows that such neurones contain granular material in some form of vacuoles. These structures may correspond to secretory granules or lysosome-related autophagic vacuoles. There is no evidence for the former notion, but it has been reported recently that the granulovacuoles are indeed autophagic vacuoles,26and there have been several experimental findings which indicate that ubiquitin-protein conjugates are enriched in the lysosomes of different cell types including n e u r o n e ~ . Quantitative ~~J~ electron microscopy shows that ubiquitinprotein conjugates may be enriched some 10-12-fold in the lysosomes of normal fibroblasts.’ As well as ubiquitin-protein conjugates some free ubiquitin has been detected in lysosomes by immunogold microscopy.27 These experimental findings underpin the notion that ubiquitin-protein conjugates in hippocampal neurones in Alzheimer’s disease are probably in some form of lysosomerelated autophagic vacuole. The ubiquitin-protein deposits that have been described as “dot-like immunoreactivity” in the neuropil and which increase in density both in normal ageing.’ and in s ~ also ~ ~ ~lysosome-related ~ bodies. The coarse ubiquitinneurodegenerative d i s e a ~ e are protein deposits observed immunohistochemically adjacent to amyloid plaques in Alzheimer’s disease2 and in scrapie-infected mouse brain probably represent pleiomorphic lysosomes in dystrophic neurites surrounding the amyloid plaques.28This notion is reinforced by immunohistochemical and histochemical observations that coarse deposits (similar to those observed by ubiquitin immunocytochemistry) corresponding to several lysosomal cathepsins can be detected in the periphery of amyloid plaques in Alzheimer’s disease. The enzymes appear to spill out from the lysosome-related structures into the plaque periphery.30 In summary, light microscopy with sensitive immunohistochemical techniques has indicated that there are at least three forms of ubiquitin-protein deposit in the human idiopathic and human and animal transmissible neurodegenerative diseases. The initial observations concentrated on the association of ubiquitin-protein deposits with flamentous inclusions; the molecular nature of these deposits is currently unknown. Ubiquitin immunohistochemistry has also revealed dot-like structures, within and adjacent to neuronal cell bodies and in the neuropil, which correspond to some form of pleiomorphic lysosome-related organelles. Finally, the finding of both ubiquitinprotein deposits and lysosomal cathepsins in coarse distorted structures adjacent to amyloid plaques suggests that pleiomorphic lysosomes are in dystrophic neurites in the plaque periphery. Lysosomes are therefore likely to play an important role in both idiopathic and transmissible neurodegenerative diseases. Recently, as noted below, a central role for lysosomes has been put forward in the generation of spongiform change in a prion encephalopathy, scrapie-infectedmouse brain, based on immunogold electron microscope studies.l2

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Ubiquitin immunohistochemistry predictively shows ubiquitin-protein conjugates in coarse deposits surrounding PrP (prion or protease resistant protein) plaques in mouse brain infected with the ME7 strain of scrapie. There are also coarse dot-like structures adjacent to neuronal perikarya (which may be large intraneuronal autophagic vacuoles or lysosome-relatedorganelles in axosomatic processes abutting onto neuronal perikarya) and dot-like structures in the n e ~ r o p i lAgain . ~ therefore as in the idiopathic neurodegenerative diseases there are at least three types of ubiquitin-protein deposits in diseased brain. Immunogold electron microscopy reveals the central role of lysosome-related organelles in scrapie-infected mouse brain. Gold particles corresponding to ubiquitinprotein conjugates can be seen to decorate dense pleiomorphic multivesicular bodies (FIG.1A) and tubulovesicular bodies in the neuropil in scrapie-infected mouse brain (FIG.1B). These types oforganelles probably represent different stages in the condensation of endosome-like structures into denser lysosome-related bodies. Large numbers of gold particles can also be seen to decorate the remnant of a dense lysosome-related organelle in an area of rarefaction which appears to be the beginning of an area of spongiform change (FIG.2). The disruption of lysosomes and release of lysosomal enzymes thus appears to be a cause of the tissue lesions in prion encephalopathies.12 The dense lysosome-related remnant is adjacent to a large spongiform lesion. Gold particles are generally not abundant in association with the larger lesions. Ubiquitin-protein conjugates are found not only in vesicular bodies in neuritic processes in the neuropil (corresponding to the dot-like structures revealed at light microscope level) but also in pleiomorphic vesicular bodies adjacent to neuronal perikarya (FIG.3A) as well as in microtubule bearing axons near to nerve cell bodies (FIG. 3B). The pleiomorphic multivesicular bodies adjacent to neurones correspond to the coarse deposits of ubiquitin-protein conjugates visualized by ubiquitin immunocytochemistry5 and represent lysosome-related bodies in axosomatic processes. Gold particles corresponding to a lysosomal marker enzyme, @-glucuronidaseare seen in lysosome-related dense bodies adjacent to large spongiform lesions as well as with debris in areas of spongiosis.12Heat-shock 70 cognate proteins have been shown to be involved in the uptake of proteins into lysosomes in stressed cells.jl Gold particles specific for a heat-shock protein 70 (hsp 70) can be seen both spilling from dense bodies beside small areas of rarefaction and again associated with debris in a large spongiform area. l2 Presumably, distended pleiomorphic lysosome-related vesicular bodies rupture to release the hsp 70. These observations on the distribution of /3glucuronidase and hsp 7012 support those on ubiquitin-protein conjugates; release of proteins from lysosome-related dense vesicular bodies leads to the generation of the earliest type of spongiform lesions in the prion encephalopathies. The reason for the disruption of lysosomal organelles in scrapie-infectedbrain may be that the abnormal isoform of the prion protein ( P P ) accumulates in neuronal lysosome-related dense bodies. The PrP" can be specifically detected by imrnunogold electron microscopy with special fixation and processing procedures employing guanidinium thiocyanate.j2The PrP" can be seen in dense bodies in the neuropil and in dense bodies in axonsL2as well as in secondary lysosome remnants in areas of rarefaction (FIG.4).The PrP" is therefore present inside lysosome-related organelles: progressive accumulation of PrP" in these structures may lead to the disruptive events indicated by the distribution of immunospecific gold particles corresponding to ubiquitin-protein conjugates, P-glucuronidase and hsp 70.l2 None of the lysosome-related organelles seen in scrapie-infected mouse brain is visible in noninfected controls.

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FIGURE 1. Immunogold electron microscopy of ubiquitin-protein conjugates in neuron2 processes in mouse brain infected with scrapie. (A) Pleiomorphic lysosome-related multivesicular body. Magnification 93120X . (B) Lysosome-related tubulovesicular body. Magnification 1044oox.

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FIGURE 4. Immunogold electron micrograph demonstrating the distribution of PrIk in the brains of mice infected with scrapie. Immunospecific gold particles can be seen in a secondary lysosome in an area of vacuolar degeneration. Magnification 50400~.

The immunogold microscopical studies on scrapie-infected mouse brain provide the in vim corroboration of in p i h o studies on scrapie-infected neuroblastoma cells, where P r F is seen to accumulate in lysosome-related organelle^.^^*^^

Lysosomes as Key Organelles in the Prion Encephalopathies The transmissible encephalopathies pose a fascinating set of problems for modern molecular biology in that an enormous amount of effort has failed to find nucleic acid associated with the infectious agent. We are therefore faced with a transmissible genetic disease where the mode of replication of the infective agent is unknown.34The agent is likely to be a novel type of infectious particle based o n the PrP" isoform of the normal cell protein PrP. The basic problems are therefore: where can infectious particles containing PrP" form and how can the PrP" be produced in the infected cells? The demonstration that PrP" is found in lysosome-related organelles both in infected cells32,33 and in brain tissueL2may provide the answers to these questions. The lysosome-endosome system is a site for the generation of the PrP" from PrF. The interior milieu of the lysosome-related organelles provides the ideal environment for

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adventitious protein-protein interactions which will result in the "hijacking" of P r F by secondary structural interactions with P r P to result in the biogenesis of more PrP": the lysosome can serve in this way as a "bioreactor" for PrP" formation. The bioreactor hypothesis is based on several facts together with the immunohistochemical and immunocytochemical observations reported here. which will be internalP r P is a phosphatidyl glycan-anchored membrane ized into the endosome-multivesicular body-lysosome system for normal degradation to amino acids. The internal milieu of lysosome-related organelles is acidic, possibly oxidizing and hydrolytic. Proteins entering this system will be subjected to unfolding prior to degradation to expose surfaces able to undergo adventitious secondary structural interactions with other protein molecules. The infective agent containing PrP", which is introduced into the brain (or other organs) by infection or experimentally, will enter neurones (and other cell types) by phagocytosis. The phagocytosed material system and bring the abnormal will enter the endosome-multivesicular-bodylysosome P r P " together with PrF, entering for normal degradation, in the same topological space. In this way the lysosome-related system will contain molecular species and aggregates capable of the secondary structural interactions to produce more P r P . The lysosomal system is probably the only topological space in cells with the properties to act as a bioreactor for the generation of more PrP". The accumulation of increasing quantities of PrP"in multivesicular and tubulovesicular bodies will eventually result in the rupture of the lysosomal membranes, and concomitant release of functional markers (ubiquitin-protein conjugates and hsp 70) and lysosomal hydrolases (P-glucuronidase). Many of the released hydrolases will retain enzyme activity at neutral p H and cause cellular damage. Some released PrP" will reenter intact lysosomes by autophagy and initiate further P r P biogenesis. Eventually, the neuronal plasma membranes will be disrupted leading to release of PrP" which can be phagocytosed by many neurones (and other cell types) to initiate further rounds of PrP" biogenesis. Repeated cycles of this process may lead to areas of rarefaction and spongiform change. The degree of spongiform change differs in natural variants of transmissible encephalopathies (eg., scrapie, Creutzfeldt-Jakob disease and GerstmannStraussler Scheinker syndrome) and experimental "strains" of transmissible agent, reflecting progression of the complex events described above in response to alternative forms of PrP" aggregate presented in the various natural diseases or experimental conditions. Neurones may eject amyloidogenic PrP" by multivesicular body-plasma membrane f i ~ s i o nand ~ ~merely die, generating gliosis without spongiform lesions in some disease variant^.^' Lysosomal involvement in PrP" biogenesis offers another mechanism not possible in other organelles and which may catalyze the formation of the abnormal isoform of P r F . Lysosomes are the cellular repository of many hydrolases involved in complex protein degradation (eg., proteases, phospholipases, glycanases, etc.). These hydrolases catalyze a series of sequential catabolic steps, any of which may generate a protein-glycan fragment of P r F or P r P which could nucleate secondary structural interactions with intact or fragmented P r P or PrP" molecules to generate more of the abnormal PrP". Protein fragments would only need to be present in small quantities (perhaps analytically difficult or impossible to detect) in growing P r P " aggregates much like the single reducing glucose residue at the centre of each space-limited disc in a glycogen molecule. Recent immunohistochemical evidence13 indicates that in a particular model of scrapie-infected mouse brains, ubiquitin-protein conjugates can be observed early afkr infection in fine dot-like structures. The ubiquitin-protein deposits which serve to detect lysosome-like bodies are first seen at essentially the same short period after infection at which PrP" can be detected by Western blotting. These studies show

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that lysosome-related organelles are intimately related to PrP" generation. There also appears to be some form of exponential process occurring in the brain since the number of lysosome-relatedbodies increases only slowly until the later stages of disease progression when there is a rapid, large increase in dot-like structures and other pathological changes. Finally, spongiosis is not confined to transmissible encephalopathies. Spongiform change is seen in specific brain regions in Alzheimer's disease38and diffuse Lewy body disease.39It is possible, therefore, that the chain ofevents triggered by one membraneassociated protein, PrP" may also occur during the lysosomal processing of another, the amyloid precursor protein (APP) to give the amyloidogenic fragments (/3/A4). Recent evidence suggests that the fragmentation of APP to generate amyloidogenic fragments occurs in the endosome-lysosomesystemMAccumulation of intralysosomd /3/A4 amyloid could cause the disruptive-lyticevents previously described. Since multivesicular bodies are known to fuse with the plasma membrane of cells36amyloidogenic A 4& ' could be ejected in this way to initiate the formation of extracellular plaques.

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12. LASZLO,L., J. LOWE, T. SELF,N. KENWARD,M. LANDON,T. MCBRIDE,C. FARQWHAR, J. BROWN, J. HOPE&R. J. ~ Y E R 1992. . Lysosornesare keyorganelles I. MCCONNELL, in the pathogenesis of prion encephalopathies. J. Pathol. 166. In press. N. KENWARD,M. LANDON,J. BROWN,J. HOPE& R. J. MAYER. 13. LOWE, J., J. FERGWSSON, 1992. Immunoreactivity to ubiquitin-protein conjugates is present early in the disease process in the brains of scrapie infected mice. J. Pathol. 168. In press. 14. MORI, H., J. KONDO& Y. IHARA. 1987. Ubiquitin is a component of paired helical filaments in Alzheimer’s disease. Science 235: 1641-1644. 1987. Ubiquitin-protein conjugates in Alzheimer’s lesions. 15. COLE,G. M. & P. S. TIMIRAS. Neurosci. Lett. 79: 207-12. G. SHAW& V. CHAW.1987. Ubiquitin is detected in neurofibril16. PERRY,G., R. FRIEDMAN, lary tangles and senile plaque neurites of Alzheimer disease brains. Proc.Natl. Acad. Sci. USA 84: 3033-3036. 1991. A68: a major subunit 17. LEE,V. M.-Y., B. J. BALIN,L. Orvos & J. Q. TROJANOWSKI. of paired helical filaments and derivatized forms of normal tau. Science 251: 675-678. E. E. BILLETT& R. J. MAYER.1987. A putative protein18. EARL,R. T., E. H. MANGIAPANE, sequestration site involving intermediate filaments for protein degradation by autophagy. Biochem. J. 241: 815. T. SELF,J. LOWE, M. LANDON,S . SMITH,J. N. HAWTHORNE 19. LASZLO,L., J. TUCKWELL, & R. J. MAYER.1991. The latent membrane protein-1 in Epstein-Barr virus-transformed lymphoblastoid cells is found with ubiquitin-protein conjugates and heat-shock protein70 in lysosomes oriented around the microtubule organizing centre. J. Pathol. 164: 203-214. D. JEFFERSON, K. MORRELL, D. MCQWIRE,T. GRAY,M. LANDON, 20. LOWE, J., G. LENNOX, F. J. DOHERTY & R. J. MAYER.1988. A filamentous inclusion body within anterior horn neurones in motor neurone disease defined by immunocytochernical localisation of ubiquitin. Neurosci. Lett. 94: 203-210. A. DODSON,J.-M. GALLO,M. SWASH& D. M. POWER. 21. LEIGH,P. N., B. H. ANDERTON, 1988. Ubiquitin deposits in anterior horn cells in motor neurone disease. Neurosci. Lett. 93: 197-203. G., J. LOWE, K. MORRELL, M. LANDON & R. J. MAYER.1989. Anti-ubiquitin 22. LENNOX, immunocytochemistry is more sensitive than conventional techniques in the detection of diffuse Lewy body disease. J. Neurol. Neurosurg. Psychiatry 52: 67-71. & L. MATTIACE. 1990. Diffuse Lewy body disease: light 23. DICKSON,D. W., H. CRYSTAL and electron microscopic irnmunohistochemistry of senile plaques. Acta Neuropathol. 78: 572-584. L., D. SALMON, D. GALASKO & E. MASLIAH.1990. The Lewy body variant of 24. HANSEN, Alzheimer’s disease: a clinical and pathological entity. Neurology 40: 1-8. A. 1988. Ubiquitin-mediated protein degradation. J. Biol. Chem. 263: 1523725. HERSHKO, 15240. K., S. HIM, T. IIZWICA, T. YANAGISAWA& M. WATANABE. 1991. Reexamina26. OKAMOTO, tion of granulovacuolar degeneration. Acta Neuropathol. 82: 340-345. A. L.,A. CIECHANOVER, R. A. BRANDT&H. J. GEUZE.1988. Immunoelec27. SCHWARTZ, tron microscopic localization of ubiquitin in hepatoma cells. EMBO J. 7: 2961-2966. E. FIER,Y. KRESS,P. DAVIES& S . H. 28. DICKSON,D. W., A. WERTKIN,L. A. MATTIACE, YEN. 1990. Ubiquitin immunoelectron microscopy of dystrophic neurites in cerebellar senile plaques of Alzheimers disease. Acta Neuropathol. 79: 486-493. A,, A. AT~ANASIO, M. C. VIGLIANI & D. SCHIFFER. 1991. Dystrophic neurites 29. MIGHELI, disease around amyloid plaques of human patients with Gerstmann-Straussler-Scheinker contain ubiquitinated inclusions. Neurosci. Lett. 121: 55-58. A. M., P. A. PASKEVICH,E. KOMINAMI & R. A. NIXON.1991. Lysosornal 30. CATALDO, hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer disease. Proc. Natl. Acad. Sci. USA 88: 10998-11002. C. PLANT& J. F. DICE. 1989. A role for a 70 kilodalton 31. CHIANG,H.-I., S. TERLECKY, heat shock protein in lysosomal degradation of intracellular proteins. Science 246: 282284.

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32. MCKINLEY,M. P., A. TARABOUMS, L. KENAGA, D. SERBAN,A. STIEBER,S. J. DEARMOND, S. B. PRUSINER & N. GONATAS.1991. Ultrastructural localisation of scrapie prions in cytoplasmic vesicles of infected cultured cells. Lab. Invest. 65: 622-630. 33. CAUGHEY, B., G. J. RAYMOND,D. ERNST& R. E. RACE. 1991. N-terminal trunction of the scrapie-associated form of PrP by lysosomal protease(s): implications regarding the site of conversion of PrP to the protease-resistant state. J. Virol. 65: 6597-6606. S. B. 1991. Molecular biology of prion diseases. Science 252: 1515-1522. 34. PRUSINER, 35. STAHL,N., D. R. BORCHELT, K. K. HSIAO & S. B. PRUSINER.1987. Glycolipid modification of the scrapie prion protein. Cell 51: 229-240. R. M. JOHNSTONE & V. BENNETT.1986. Selective external36. DAVIS, J. Q., D. DANSEREAU, ization of an ATP-bindingprotein structurally related to clathrin uncoating ATP'ase heat shock protein in vesicles containing terminal transferrin receptors during reticulocyte maturation. J. Biol. Chem. 261: 15368-15371. J., F. OWEN, M. POULTER,M. LEACH,T. J. CROW, M. N . ROSSOR,J. HARDY, 37. COLLINGE, M. J. MULLAN,I. JANOTA& P. L. LANTOS.1990. Prion dementia without characteristic pathology. Lancet 336: 7-9. & D. A. DRACHMAN.1987. Vacuolar change 38. SMITH,T. N., U. ANWER,U. DEGIROLAMI in Alzheimer's disease. Arch. Neurol. 44: 1225-1228. 39. HANSEN,L. A., E. MASLIAH,R. D. TERRY & S. S. MIRVA.1989. A neuropathological subset of Alzheimer's disease with concomitant kwy body disease and spongiform change. Acta Neuropathol. 78: 194-201. S. G. YOUNKIN. 1992. Processing 40. GOLDE,T. E., S. Esms, L. H. YOUNKIN, D. J. SELKOE& of the amyloid precursor protein to potentially amyloidogenic derivatives. Science 255: 728-730.

Ubiquitin, lysosomes, and neurodegenerative diseases.

Ubiquitin, Lysosomes, and Neurodegenerative Diseasesa R. JOHN MAYE&&LAJOS LASZLO,& MICHAEL LANDON,’ JAMES HOPE: AND JAMES LOWE Departmmn af ‘Biochemiw...
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