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Glutamine repeats and neurodegenerative diseases
Brain Research Bulletin, Vol. 50, Nos. 5/6, p. 467, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0361-9230/99/$–see front matter
PII S0361-9230(99)00137-9
Glutamine repeats and neurodegenerative diseases Max F. Perutz* MRC Laboratory of Molecular Biology, Hills Road, Cambridge, United Kingdom [Received 26 May 1999; Accepted 26 May 1999] of neurodegenerative disorders. They appear to be caused by the aggregation of extracellular amyloid or of normally soluble proteins into intracellular, insoluble fibres: Alzheimer’s disease through formation of neurofibrillary tangles; Parkinson’s disease through aggregation of alpha-synuclein into Lewy bodies; prion diseases through aggregation of prion proteins; and a host of other amyloid diseases through aggregation of a variety of proteins. The aggregates seem to poison neurons—no matter whether they are deposited between them, in the cell cytoplasm or in the cell nucleus. We do not yet understand why, but it might be because living cells are highly organized structures and cannot tolerate disruption by protein precipitates, or because these precipitates adsorb other essential proteins [4].
Eight different inherited neurodegenerative diseases have now been found to be due to expansion of glutamine repeats in the affected proteins. With an incidence of about four in a hundred thousand, Huntington’s Chorea is the most frequent one among them. There is no homology in either size or amino acid sequence between them, and they affect different neurons, but they exhibit one striking common feature. Repeats of fewer than 37 glutamines are harmless and repeats with more than 40 cause disease, which sets in earlier and is more severe the longer the repeat. This implies that elongation causes a change of molecular structure, but we are still unsure about its nature. In vitro, peptides containing rows of glutamines associate to form beta-pleated sheets held together by hydrogen bonds between their main chain and side chain amides. It occurred to me that this property might provide the clue to the molecular mechanism of the diseases, because it would cause the affected proteins to form aggregates that poison the neurons [5]. Such aggregates were first found in mice made transgenic for the first exon of the Huntington gene which includes the codons for the glutamine repeat [3]. Mice with 18 glutamines remained healthy, but mice transgenic for the peptide with about 150 glutamines exhibited symptoms similar to those of the human disease. In the striatum and cortex of these mice, the cell nuclei contained granular and fibrous inclusions which stained with antibodies against the peptide and against ubiquitin [1]. Shortly afterwards, similar inclusions were found in post-mortem brains of Huntington patients [2]. They have since also been found in post-mortem brains of several of the other glutamine expansion diseases. Expression of the N-terminal Huntington peptide with 20 or 30 glutamines in Escherichia coli produced soluble proteins, but peptides with 51, 83 or 122 glutamines formed insoluble aggregates [6]. The agreement between the lengths of glutamine repeats that form aggregates in vitro and the lengths that cause disease can hardly be coincidental and strongly suggests that such aggregation is the cause of neurodegeneration. The discovery of the nuclear aggregates, which is now seen as the common cause of all the diseases due to expansion of glutamine repeats, has brought a new unity to the molecular pathology
REFERENCES 1. Davies, S. W.; Turmaine, M.; Cozens, B. A.; DiFiglia, M.; Sharp, A. H.; Ross, C. A.; Scherzinger, E.; Wanker, E. E.; Mangiarini, L.; Bates, G. P. Formation of neuronal intranuclear inclusions (NII) underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90:537–548; 1997. 2. DiFiglia, M.; Sapp, E.; Chase, K. O.; Davies, S. W.; Bates, G. P.; Vonsattel, J.-P.; Aronin, N. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277: 1990 –1993; 1997. 3. Mangiarini, L.; Sathasivam, K.; Seller, M.; Cozens, B.; Harper, A.; Hetherington, C.; Lawton, M.; Trottier, Y.; Lehrach, H.; Davies, S. W.; Bates, G. P. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506; 1996. 4. Perutz, M. F. Glutamine repeats and neurodegenerative diseases: Molecular aspects. Trends Biochem. Sci. 24:58 – 63; 1999. 5. Perutz, M. F.; Johnson, T.; Suzuki, M.; Finch, J. T. Glutamine repeats as polar zippers: Their possible role in inherited neurodegenerative disease. Proc. Natl. Acad. Sci. USA 91:5355–5358; 1994. 6. Scherzinger, E.; Sittler, A.; Schweiger, K.; Heiser, V.; Lurz, R.; Hasenbank, R.; Bates, G. P.; Lehrach, H.; Wanker, E. E. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: Implications for Huntington’s disease pathology. Proc. Natl. Acad. Sci. USA 96:4604 – 4609; 1999.
* Address for correspondence: Dr. Max F. Perutz, MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. Fax: ⫹44 1223 213556; E-mail: [email protected]
467
PII S0361-9230(99)00137-9
Glutamine repeats and neurodegenerative diseases Max F. Perutz* MRC Laboratory of Molecular Biology, Hills Road, Cambridge, United Kingdom [Received 26 May 1999; Accepted 26 May 1999] of neurodegenerative disorders. They appear to be caused by the aggregation of extracellular amyloid or of normally soluble proteins into intracellular, insoluble fibres: Alzheimer’s disease through formation of neurofibrillary tangles; Parkinson’s disease through aggregation of alpha-synuclein into Lewy bodies; prion diseases through aggregation of prion proteins; and a host of other amyloid diseases through aggregation of a variety of proteins. The aggregates seem to poison neurons—no matter whether they are deposited between them, in the cell cytoplasm or in the cell nucleus. We do not yet understand why, but it might be because living cells are highly organized structures and cannot tolerate disruption by protein precipitates, or because these precipitates adsorb other essential proteins [4].
Eight different inherited neurodegenerative diseases have now been found to be due to expansion of glutamine repeats in the affected proteins. With an incidence of about four in a hundred thousand, Huntington’s Chorea is the most frequent one among them. There is no homology in either size or amino acid sequence between them, and they affect different neurons, but they exhibit one striking common feature. Repeats of fewer than 37 glutamines are harmless and repeats with more than 40 cause disease, which sets in earlier and is more severe the longer the repeat. This implies that elongation causes a change of molecular structure, but we are still unsure about its nature. In vitro, peptides containing rows of glutamines associate to form beta-pleated sheets held together by hydrogen bonds between their main chain and side chain amides. It occurred to me that this property might provide the clue to the molecular mechanism of the diseases, because it would cause the affected proteins to form aggregates that poison the neurons [5]. Such aggregates were first found in mice made transgenic for the first exon of the Huntington gene which includes the codons for the glutamine repeat [3]. Mice with 18 glutamines remained healthy, but mice transgenic for the peptide with about 150 glutamines exhibited symptoms similar to those of the human disease. In the striatum and cortex of these mice, the cell nuclei contained granular and fibrous inclusions which stained with antibodies against the peptide and against ubiquitin [1]. Shortly afterwards, similar inclusions were found in post-mortem brains of Huntington patients [2]. They have since also been found in post-mortem brains of several of the other glutamine expansion diseases. Expression of the N-terminal Huntington peptide with 20 or 30 glutamines in Escherichia coli produced soluble proteins, but peptides with 51, 83 or 122 glutamines formed insoluble aggregates [6]. The agreement between the lengths of glutamine repeats that form aggregates in vitro and the lengths that cause disease can hardly be coincidental and strongly suggests that such aggregation is the cause of neurodegeneration. The discovery of the nuclear aggregates, which is now seen as the common cause of all the diseases due to expansion of glutamine repeats, has brought a new unity to the molecular pathology
REFERENCES 1. Davies, S. W.; Turmaine, M.; Cozens, B. A.; DiFiglia, M.; Sharp, A. H.; Ross, C. A.; Scherzinger, E.; Wanker, E. E.; Mangiarini, L.; Bates, G. P. Formation of neuronal intranuclear inclusions (NII) underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90:537–548; 1997. 2. DiFiglia, M.; Sapp, E.; Chase, K. O.; Davies, S. W.; Bates, G. P.; Vonsattel, J.-P.; Aronin, N. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277: 1990 –1993; 1997. 3. Mangiarini, L.; Sathasivam, K.; Seller, M.; Cozens, B.; Harper, A.; Hetherington, C.; Lawton, M.; Trottier, Y.; Lehrach, H.; Davies, S. W.; Bates, G. P. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506; 1996. 4. Perutz, M. F. Glutamine repeats and neurodegenerative diseases: Molecular aspects. Trends Biochem. Sci. 24:58 – 63; 1999. 5. Perutz, M. F.; Johnson, T.; Suzuki, M.; Finch, J. T. Glutamine repeats as polar zippers: Their possible role in inherited neurodegenerative disease. Proc. Natl. Acad. Sci. USA 91:5355–5358; 1994. 6. Scherzinger, E.; Sittler, A.; Schweiger, K.; Heiser, V.; Lurz, R.; Hasenbank, R.; Bates, G. P.; Lehrach, H.; Wanker, E. E. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: Implications for Huntington’s disease pathology. Proc. Natl. Acad. Sci. USA 96:4604 – 4609; 1999.
* Address for correspondence: Dr. Max F. Perutz, MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. Fax: ⫹44 1223 213556; E-mail: [email protected]
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