Aberrant Protein Deposition and Neurological Disease (1999)

spinocerebellar ataxia central nervous system Huntington disease dentatorubral-pallidoluysian atrophy spinal and bulbar muscular atrophy Alzheimer's disease neurofibrillary tangle amyloid precursor protein Parkinson's disease amyotrophic lateral sclerosis presenilin low density lipoprotein receptor-related protein The association of protein deposits with neurodegeneration has become a consistent finding in a large group of etiologically diverse diseases (1Paulson H.L. Am. J. Hum. Genet. 1999; 64: 339-345Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 2Tolnay M. Probst A. Neuropathol. Appl. Neurobiol. 1999; 25: 171-187Crossref PubMed Scopus (194) Google Scholar) (Table I). The protein deposits are generally dense fibrillar structures containing a high percentage of β-pleated sheet secondary structure and can be located in various cellular compartments as well as extracellularly. Moreover, the deposits are generally ubiquitinated and may contain numerous cellular proteins.Table INeurological disorders with aberrant protein depositionDisorderProteinAffected regionsCellular location of aggregatesIn vivoIn vitroADAmyloid-βHippocampus, cerebral cortexExtracellularNDaND, not determined.PDα-SynucleinSubstantia nigra, hypothalamusCytoplasmicNuclearPrion diseasesPrPVarious regions of CNSExtracellularNDALSSOD1Motor cortex, brainstemCytoplasmicCytoplasmicSCA1ataxin-1Purkinje cells, brainstemNuclearNuclearSCA3ataxin-3Basal ganglia, brainstemNuclear, perinuclearNuclear, perinuclearSCA6Calcium channelPurkinje cellsCytoplasmicPerinuclearSCA7ataxin-7Cerebellum, inferior oliveNuclearNuclear, nucleolarHDhuntingtinStriatum, cerebral cortexVariable intracellularVariable intracellularDRPLAatrophin-1Dentate nucleus, neocortexNuclearNuclear, perinuclearSBMAAndrogen receptorSpinal cord, cranial nervesNuclearNuclear, perinucleara ND, not determined. Open table in a new tab Currently there are eight neurodegenerative disorders known to be caused by the expansion of a CAG trinucleotide repeat coding for polyglutamine. Protein aggregates have been observed in most of these disorders (1Paulson H.L. Am. J. Hum. Genet. 1999; 64: 339-345Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar,3Ishikawa K. Fujigasaki H. Saegusa H. Ohwada K. Fujita T. Iwamoto H. Komatsuzaki Y. Toru S. Toriyama H. Watanabe M. Ohkoshi N. Shoji S. Kanazawa I. Tanabe T. Mizusawa H. Hum. Mol. Genet. 1999; 8: 1185-1193Crossref PubMed Scopus (170) Google Scholar). A mechanism of pathogenesis for these disorders has not been elucidated, although it is likely mediated through the polyglutamine tract because longer tracts lead to earlier ages of onset and more severe phenotypes. Spinocerebellar Ataxia Type 1 (SCA1)1— SCA1 is characterized clinically by gait and limb ataxia, dysarthia, dysmetria, and variable degrees of muscle wasting (4Koshy B.T. Zoghbi H.Y. Brain Pathol. 1997; 7: 927-942Crossref PubMed Scopus (102) Google Scholar). SCA1 patients have CAG repeat tracts ranging in size from 39 to 83 glutamines. TheSCA1 gene product, ataxin-1, is normally a nuclear protein except in Purkinje cells where it is also cytoplasmic. Ubiquitin-positive nuclear inclusions have been observed inSCA1 transgenic mice, transfected cells, and in affected brain regions of SCA1 patients (5Skinner P.J. Koshy B.T. Cummings C.J. Klement I.A. Helin K. Servadio A. Zoghbi H.Y. Orr H.T. Nature. 1997; 389: 971-974Crossref PubMed Scopus (499) Google Scholar) (Fig. 1). In both cultured cells and cerebellar tissue of SCA1transgenic mice, ataxin-1 associates with the nuclear matrix (5Skinner P.J. Koshy B.T. Cummings C.J. Klement I.A. Helin K. Servadio A. Zoghbi H.Y. Orr H.T. Nature. 1997; 389: 971-974Crossref PubMed Scopus (499) Google Scholar). An associated redistribution of the matrix-associated promyelocytic leukemia protein suggests that SCA1 pathogenesis may be due to morphologic changes within the nucleus. Transgenic mice expressing mutant ataxin-1 without a nuclear localization sequence fail to develop disease-related pathology and exhibit no signs of ataxin-1 aggregation (6Klement I.A. Skinner P.J. Kaytor M.D. Yi H. Hersch S.M. Clark H.B. Zoghbi H.Y. Orr H.T. Cell. 1998; 95: 41-53Abstract Full Text Full Text PDF PubMed Scopus (891) Google Scholar). Interestingly, other transgenic mice lacking a self-association domain outside of the polyglutamine tract express mutant ataxin-1 in the nucleus and develop ataxia without evidence of ataxin-1 nuclear aggregates. Thus, nuclear localization of mutant ataxin-1 appears to be required for pathogenesis, whereas visible nuclear aggregation may not be required. Spinocerebellar Ataxia Type 3/Machado-Joseph Disease (SCA3/MJD)—Clinically, SCA3 patients present with progressive ataxia, external ophthalmoplegia, muscle atrophy, and parkinsonian signs (4Koshy B.T. Zoghbi H.Y. Brain Pathol. 1997; 7: 927-942Crossref PubMed Scopus (102) Google Scholar). These patients typically have repeat tract expansions ranging from 55 to 84 glutamines. Ataxin-3 is normally a cytoplasmic protein that accumulates in ubiquitinated aggregates in the nuclei of affected neurons (7Paulson H.L. Das S.S. Crino P.B. Perez M. Patel S.C. Gotsdiner D. Fischbeck K.H. Pittman R.N. Am. Neur. Assoc. 1997; 41: 453-462Crossref Scopus (236) Google Scholar). A necessary event in SCA3 pathogenesis is the entry of expanded ataxin-3 into the nucleus. Ubiquitinated intranuclear neuronal inclusions were only seen in neurons and not within glial cells, even though glial cells are immunoreactive with ataxin-3 antibodies. Cells expressing a truncated ataxin-3 fragment produce intranuclear inclusions, recruit full-length ataxin-3 into aggregates, and exhibit an induction of cell death (8Perez M.K. Paulson H.L. Pendse S.J. Saionz S.J. Bonini N.M. Pittman R.N. J. Cell Biol. 1998; 143: 1457-1470Crossref PubMed Scopus (279) Google Scholar). An ataxin-3 fragment may serve to catalyze the formation of intranuclear aggregates by translocating into the nucleus and recruiting endogenous ataxin-3 and other proteins into aggregates, in a dominant-negative manner. Spinocerebellar Ataxia Type 6 (SCA6)—SCA6 is an autosomal dominant cerebellar ataxia caused by a CAG repeat expansion within the 3′-region of the α1A voltage-dependent calcium channel gene (CACNA1A) (9Zhuchenko O. Bailey J. Bonnen P. Ashizawa T. Stockton D.W. Amos C. Dobyns W.B. Subramony S.H. Zoghbi H.Y. Lee C.C. Nat. Genet. 1997; 15: 62-69Crossref PubMed Scopus (1441) Google Scholar). Unlike the other CAG repeat expansion disorders, expansions within SCA6 patients are relatively small (21–30 glutamines) and fall within the normal range of other CAG tract lengths. In SCA6 brains numerous protein aggregates, appearing not to be ubiquitinated, were observed exclusively in the cytoplasm of Purkinje cells (3Ishikawa K. Fujigasaki H. Saegusa H. Ohwada K. Fujita T. Iwamoto H. Komatsuzaki Y. Toru S. Toriyama H. Watanabe M. Ohkoshi N. Shoji S. Kanazawa I. Tanabe T. Mizusawa H. Hum. Mol. Genet. 1999; 8: 1185-1193Crossref PubMed Scopus (170) Google Scholar). Unlike this cytoplasmic localization, cells transfected with expanded SCA6 constructs exhibit perinuclear aggregates leading to apoptotic cell death. Spinocerebellar Ataxia Type 7 (SCA7)— CAG repeat tract expansions in SCA7 patients have been shown to range from 34 to greater than 200 glutamines (1Paulson H.L. Am. J. Hum. Genet. 1999; 64: 339-345Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). In the brain of an early onset patient, intranuclear neuronal ubiquitinated inclusions occurred most frequently in the inferior olivary complex, a site of severe neuronal loss in SCA7 patients (10Holmberg M. Duyckaerts C. Durr A. Cancel G. Gourfinkel-An I. Damier P. Faucheux B. Trottier Y. Hirsch E.C. Agid Y. Brice A. Hum. Mol. Genet. 1998; 7: 913-918Crossref PubMed Scopus (303) Google Scholar). However, inclusions were also observed in regions not affected by the disease, suggesting some cell specificity regarding the consequence of aggregation. Generally, inclusions in SCA7 brains were shown to be ubiquitinated to varying degrees. A critical observation is that the inclusions that are not ubiquitinated are found in regions that are not affected, suggesting ubiquitination is required for neurodegeneration. Similarly, ataxin-7 aggregates in Cos-1 cells that are localized to the nucleus are not ubiquitinated (11Kaytor M.D. Duvick L.A. Skinner P.J. Koob M.D. Ranum L.P.W. Orr H.T. Hum. Mol. Genet. 1999; 8: 1657-1664Crossref PubMed Scopus (96) Google Scholar). Hence, some cell specificity with regard to ubiquitination also occurs. Huntington Disease (HD)— The HD gene product, huntingtin, is predominantly a cytoplasmic protein (12Ross C.A. Becher M.W. Colomer V. Engelender S. Wood J.D. Sharp A.H. Brain Pathol. 1997; 7: 1003-1016Crossref PubMed Scopus (55) Google Scholar). HD patients have CAG repeat tract lengths ranging from 38 to 180 glutamines. Nuclear inclusions in HD patients and transgenic mice have been found both in non-CNS tissue and neurons (13Sathasivam K. Hobbs C. Turmaine M. Mangiarini L. Mahal A. Bertaux F. Wanker E.E. Doherty P. Davies S.W. Bates G.P. Hum. Mol. Genet. 1999; 8: 813-822Crossref PubMed Scopus (235) Google Scholar). Generally, the inclusions are immunoreactive with anti-N-terminal huntingtin and ubiquitin antibodies (Fig. 1). The striatum, which is predominantly affected in HD, actually contains far fewer aggregates compared with the cortex (14Gutekunst C.-A. Li S.-H. Yi H. Mulroy J.S. Kuemmerle S. Jones R. Rye D. Ferrante R.J. Hersch S.M. Li X.-J. J. Neurosci. 1999; 19: 2522-2534Crossref PubMed Google Scholar). This suggests that huntingtin aggregates may not be a good indicator of cells destined to die in HD (15Kuemmerle S. Gutekunst C.-A. Klein A.M. Li X.-J. Li S.-H. Beal M.F. Hersch S.M. Ferrante R.J. Ann. Neurol.,. 1999; (in press)PubMed Google Scholar). Interestingly, non-ubiquitinated aggregates have been found, suggesting that ubiquitination occurs late in formation. Because there is no obvious nuclear localization sequence in huntingtin known nuclear import mechanisms are not responsible for translocating huntingtin to the nucleus. However, proteolytic processing may produce a smaller protein fragment that can enter the nucleus by diffusion (16Hackam A.S. Singaraja R. Zhang T. Gan L. Hayden M.R. Hum. Mol. Genet. 1999; 8: 25-33Crossref PubMed Scopus (77) Google Scholar). The activation of caspases appears to be involved in proteolytic cleavage, which leads to apoptotic cell death (17Sanchez I. Xu C.-J. Juo P. Kakizaka A. Blenis J. Yuan J. Neuron. 1999; 22: 623-633Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar, 18Ona V.O. Li M. Vonsattel J.P.G. Andrews L.J. Khan S.Q. Chung W.M. Frey A.S. Menon A.S. Li X.-J. Stieg P.E. Yuan J. Penney J.B. Young A.B. Cha J.-H.J. Friedlander R.M. Nature. 1999; 399: 263-267Crossref PubMed Scopus (577) Google Scholar). In addition, numerous reports have shown a correlation between the length of a truncated huntingtin protein and the size of the CAG tract with the frequency and localization of aggregates (19Rubinsztein D.C. Wyttenbach A. Rankin J. J. Med. Genet. 1999; 36: 265-270PubMed Google Scholar). Interestingly, transfection studies have shown that changing the subcellular localization of the huntingtin does not alter the frequency of aggregation or the level of toxicity (16Hackam A.S. Singaraja R. Zhang T. Gan L. Hayden M.R. Hum. Mol. Genet. 1999; 8: 25-33Crossref PubMed Scopus (77) Google Scholar). In contrast, HDconstructs transfected into cultured striatal neurons produce intranuclear inclusions that do not correlate with apoptotic cell death (20Saudou F. Finkbeiner S. Devys D. Greenberg M.E. Cell. 1998; 95: 55-66Abstract Full Text Full Text PDF PubMed Scopus (1371) Google Scholar). Dentatorubral-Pallidoluysian Atrophy (DRPLA)—The clinical features of DRPLA are similar to HD (12Ross C.A. Becher M.W. Colomer V. Engelender S. Wood J.D. Sharp A.H. Brain Pathol. 1997; 7: 1003-1016Crossref PubMed Scopus (55) Google Scholar). The DRPLA gene product, atrophin-1, is normally a cytoplasmic protein that is found in ubiquitinated neuronal intranuclear inclusions in affected brain regions (1Paulson H.L. Am. J. Hum. Genet. 1999; 64: 339-345Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). Expansions of the CAG tract in atrophin-1 range from 49 to 88 glutamines. Caspase cleavage of atrophin-1 has been shown to modulate cell toxicity and aggregate formation (21Ellerby L.M. Andrusiak R.L. Wellington C.L. Hackam A.S. Propp S.S. Wood J.D. Sharp A.H. Margolis R.L. Ross C.A. Salvesen G.S. Hayden M.R. Bredesen D.E. J. Biol. Chem. 1999; 274: 8730-8736Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). Cleavage is necessary for cell toxicity because mutation of the caspase cleavage site within atrophin-1 suppresses aggregate formation. In cells expressing truncated atrophin-1 with an expanded repeat, perinuclear ubiquitinated aggregates and apoptotic cell death were observed (22Igarashi S. Koide R. Shimohata T. Yamada M. Hayashi Y. Takano H. Date H. Oyake M. Sato T. Sato A. Egawa S. Ikeuchi T. Tanaka H. Nakano R. Tanaka K. Hozumi I. Inuzuka T. Takahashi H. Tsuji S. Nat. Genet. 1998; 18: 111-117Crossref PubMed Scopus (340) Google Scholar). Interestingly, the full-length expanded protein did not form aggregates but was drawn into the aggregates containing the truncated protein. This interaction could be stabilized by a transglutaminase-catalyzed reaction (23Kahlem P. Terre C. Green H. Djian P. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14580-14585Crossref PubMed Scopus (180) Google Scholar). Spinal and Bulbar Muscular Atrophy (SBMA)—SBMA is an X-linked recessive disorder caused by expansions of a polyglutamine repeat, ranging from 38 to 65 CAGs, in the androgen receptor (4Koshy B.T. Zoghbi H.Y. Brain Pathol. 1997; 7: 927-942Crossref PubMed Scopus (102) Google Scholar). Patients typically exhibit slow, progressive weakness and atrophy. Ubiquitinated inclusions have been observed in motor neurons of SBMA patients and in transfected cells (1Paulson H.L. Am. J. Hum. Genet. 1999; 64: 339-345Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 24Merry D.E. Kobayashi Y. Bailey C.K. Taye A.A. Fischbeck K.H. Hum. Mol. Genet. 1998; 7: 693-701Crossref PubMed Scopus (166) Google Scholar). Cytoplasmic protein aggregation in transfected cells was not observed unless truncatedSBMA constructs were used. The transfected SBMAgene product was shown to undergo proteolytic processing in transfected cells, possibly producing fragments due to cleavage within the CAG tract (25Butler R. Leigh P.N. McPhaul M.J. Gallo J.-M. Hum. Mol. Genet. 1998; 7: 121-127Crossref PubMed Scopus (70) Google Scholar). The appearance of this cleavage product, formation of cytoplasmic aggregates, and increased cell toxicity occurred in a repeat tract length-dependent manner. AD is characterized by the accumulation of extracellular plaques and cytoplasmic neurofibrillary tangles (NFTs) (2Tolnay M. Probst A. Neuropathol. Appl. Neurobiol. 1999; 25: 171-187Crossref PubMed Scopus (194) Google Scholar). The major component of the dense plaques is β-amyloid (Aβ), a 39–43-amino acid peptide derived from the larger amyloid precursor protein (APP). Accumulation of Aβ is an early event in development of AD that may precede other brain lesions and symptoms by years. NFTs are bundles of paired helical filaments containing highly phosphorylated and ubiquitinated forms of the microtubule-associated factor tau (26Morishima-Kawashima M. Hasegawa M. Takio K. Suzuki M. Titani K. Ihara Y. Neuron. 1993; 10: 1151-1160Abstract Full Text PDF PubMed Scopus (291) Google Scholar). Tissue-specific processing results in heterogeneity of the Aβ peptide at both its N and C termini (27Wisniewski T. Ghiso J. Frangione B. Neurobiol. Dis. 1997; 4: 313-328Crossref PubMed Scopus (167) Google Scholar). Both β- and γ-secretase have been shown to cleave APP, but this cleavage is not likely the first pathological alteration in AD because peptide resulting from this cleavage is found in deposits and in most other cells (28Selkoe D.J. Annu. Rev. Cell Biol. 1994; 10: 373-403Crossref PubMed Scopus (747) Google Scholar). The accumulation of Aβ is considered to be a central part of AD pathogenesis, which implies that over time preamyloid deposits are “transformed” into amyloid plaques (29Hardy J. Ann. Med. 1996; 28: 255-258Crossref PubMed Scopus (62) Google Scholar). These lesions are thought to become compacted over a number of years while taking on the characteristics of amyloid and are associated with neuronal damage and tangles in the form of neuritic plaques. 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D. M.F. D. S. Nat. Genet. 1997; PubMed Scopus Google Scholar). in with a of Hence, mutation of may lead to abnormal of proteins involved in early onset recessive has been associated with mutations in the gene T. S. N. H. Y. S. M. Y. N. Nature. 1998; PubMed Scopus Google Scholar). The is to in the ubiquitin protein are responsible for an form of T. M. J. Nat. Genet. 1997; 15: PubMed Scopus Google Scholar). protein aggregates neurodegeneration or are the result of a is not In the CAG repeat disorders, aggregates precede the onset of symptoms (19Rubinsztein D.C. Wyttenbach A. Rankin J. J. Med. Genet. 1999; 36: 265-270PubMed Google Scholar). Interestingly, small aggregates are not ubiquitinated, that ubiquitination occurs late in the formation (14Gutekunst C.-A. Li S.-H. Yi H. Mulroy J.S. Kuemmerle S. Jones R. Rye D. Ferrante R.J. Hersch S.M. Li X.-J. J. Neurosci. 1999; 19: 2522-2534Crossref PubMed Google Scholar). This suggests that the cell is to the proteins but is The to the aggregate may the to normal protein processing and which could lead to of it may be that in the of cell the is to changes in the of protein and which may lead to neurodegeneration. and Li for critical of the