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Tangled triplets: intranuclear inclusions in Huntington's disease
Literature
alleles are a necessary, but not a sufficient predisposing factor, and triggering factors are also involved in the transition to disease. The nature of these trigger factors has been the subject of much debate; candidates range from the action of other genes to infectious agents. In this report, the expression of a particular gene from an endogenous retrovirus has been implicated as the trigger to IDDM in susceptible individuals . The road to this work was laid out in 1994 with the discovery of the selective expansion of a particuar type of T-cell receptor in IDDM patients. This implicated the involvement of a pancreatic cell membrane-bound superantigen. Superantigens can stimulate high proportions of T cells and they are unique products of microorganisms. In this work, Conrad et al. (1994) demonstrated reverse transcriptase activity in cultured islets from pancreatic IDDM lesions. This, together with previous work describing retrovirus-encoded superantigens, led Conrad et al. (1997) to search for retroviral candidates in IDDM patients. By using methods of specific amplification, the authors identified and isolated a novel fulllength retroviral genome from cell cultures prepared from IDDM patients, but not from healthy control individuals. This endogenous retrovirus, called IDDMK,.222, is a member of the HERV-K (human endogenous retrovirus) class related to the mouse mammary tumour virus (MMTV) . MMTVs have been shown previously to encode superantigens, and the putative superantigen function encoded by IDDMK,.222 was identified. Using a series of deletion mutants, this was subsequently localized to the N-terminus of the IDDMK , .~ 2 envelope protein. Interestingly, this contrasts with the superantigen of MMTV, which is encoded by an open reading frame in the 3' long terminal repeat. These superantigens do not share any sequence homology, nor does the IDDMK,.222 superantigen show any similarity to cellular proteins implicated in IDDM autoimmunity. The role of this superantigen in the development of IDDM is suggested to be activation of a subset of auto reactive T cells in genetically predisposed individuals; these subsequently migrate to the pancreatic tissue and instigate cellspecific death. That the retrovirus-encoded superantigen constitutes a candidate autoimmune gene is a novel idea, because it has the potential to be transmitted as either an inherited trait or an infectious agent. The next step in this quest will be to determine whether this superantigen is the direct cause of disease. There is an accumulation of circumstantial evidence for retroviral involvement in autoimmune disease: recently, retroviruses have been connected to multiple sclerosis [Perron , H.
422
MOL C
et al. (1997) Proc. Nat!. Acad. Sci. U. S. A. 94, 7583- 7588] and Sjogren's syndrome [Griffiths, D.J. et al. (1997) J. Virol. 71 , 2866-2877] . Exposure to retroviral superantigens as a triggering event in autoimmune phenomena is a compelling hypothesis that will , no doubt, lead to further investigations, focusing multidisciplinary approaches to study autoimmunity. Roger Hewson PhD Centre for Applied Microbiology and Research, Porton Down, Salisbury, Wiltshire, UK SP4 OJG .
Tangled triplets: intranuclear inclusions in Huntington's disease Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation Davies, SW et al. (1997)
LAR M E D I C I N E TODAY, O CTOB E R 1997
intranuclear inclusions containing both mutant protein and ubiquitin, increased nuclear indentations and increased number and clustering of nuclear pores. These changes preceded the development of neurologic abnormalities and were most prominent in cortex and striatum, the structures most affected by HD pathology. Similar changes have been described in biopsy specimens from HD patients. Scherzinger et al. expressed and purifed a series of fusion proteins of glutathione-S-transferase (GST) and the same portion of the huntingtin gene (exon 1) containing a polyglutamine expansion of 20-122 glutamines. In vitro , fusion peptides with larger polyglutamine segments formed insoluble complexes that resembled purified amyloid when examined by electron microscopy. Large insoluble proteins containing huntingtin epitopes were also detected in nuclear extracts of brain and, to a lesser ex1ent, liver from mice transgenic for exon 1 of huntingtin with 145 glutamines. These aggregates were not detected in the cy1osol or in nontransgenic littermates. Although neither of these studies prove that intranuclear inclusions or aggregates of abnormal huntingtin protein cause neuronal damage in HD, they raise the hypothesis that HD, and other CAG repeat disorders, might result from abnormal aggregation of normally Cy10plasmic proteins in the nuclei of affected neurons.
Cell 90, 537-548
Huntingtin-encoded polyglutamine expansions form amylOid-like protein aggregates in vitro and in vivo Scherzinger, E. et al. (1 997)
B. Joy Snider MD, PhD Instructor in Neurology, Dept of Neurology and Neurological Surgery, CSNSI, Washington University School of Medicine, Box 8111 , 660 S. Euclid Avenue, St Louis, MO 63110-1 093, USA.
Cell 90, 54~58 Huntington's disease (HD), dentatorubral and pallidoluysian atrophy and spinocerebellar ataxia (SCA 1, 2 and 3) are characterized by expanded segments of CAG trinucleotide repeats in the protein-coding regions of the affected genes. The CAG codons are translated into glutamines in the resulting proteins; how expansion of the repeat above a critical level (35-40 glutamines) causes disease in specific brain regions is still unknown, particularly as the genes are widely expressed outside the nervous system. Davies et al. generated a number of mouse lines transgenic for exon 1 of the human HD gene with 18- 156 CAG repeats . Mice with 115 or more repeats developed a neurodegenerative disorder reminiscent of human HD. Electron microscopic (EM) study of the brains of these mice showed prominent changes in neuronal nuclei, including opyright
The I8raIure page Is deeigned to alert readers to recant prinwy papers that . . important to biomedical reparticuB1r inncMdIve, likely to hIM IigIIIbnt cInIcaI impIct, or ccRnMrIIa A . . . d aeniar active re.aarcherlll COIIII1llllaued to aeIect one or two paperI paMahed k1 the last WIIkIIhit itwi*' their . . of ex...... If you .. Inanstad In Jc*1i1g
.'ardIn,
*
.................. ,.,..to the Mar at
1997 Ehevier cicncc LId. All righ ts rc,crvcd. 1357 - 43 10/97/$ 17.00
alleles are a necessary, but not a sufficient predisposing factor, and triggering factors are also involved in the transition to disease. The nature of these trigger factors has been the subject of much debate; candidates range from the action of other genes to infectious agents. In this report, the expression of a particular gene from an endogenous retrovirus has been implicated as the trigger to IDDM in susceptible individuals . The road to this work was laid out in 1994 with the discovery of the selective expansion of a particuar type of T-cell receptor in IDDM patients. This implicated the involvement of a pancreatic cell membrane-bound superantigen. Superantigens can stimulate high proportions of T cells and they are unique products of microorganisms. In this work, Conrad et al. (1994) demonstrated reverse transcriptase activity in cultured islets from pancreatic IDDM lesions. This, together with previous work describing retrovirus-encoded superantigens, led Conrad et al. (1997) to search for retroviral candidates in IDDM patients. By using methods of specific amplification, the authors identified and isolated a novel fulllength retroviral genome from cell cultures prepared from IDDM patients, but not from healthy control individuals. This endogenous retrovirus, called IDDMK,.222, is a member of the HERV-K (human endogenous retrovirus) class related to the mouse mammary tumour virus (MMTV) . MMTVs have been shown previously to encode superantigens, and the putative superantigen function encoded by IDDMK,.222 was identified. Using a series of deletion mutants, this was subsequently localized to the N-terminus of the IDDMK , .~ 2 envelope protein. Interestingly, this contrasts with the superantigen of MMTV, which is encoded by an open reading frame in the 3' long terminal repeat. These superantigens do not share any sequence homology, nor does the IDDMK,.222 superantigen show any similarity to cellular proteins implicated in IDDM autoimmunity. The role of this superantigen in the development of IDDM is suggested to be activation of a subset of auto reactive T cells in genetically predisposed individuals; these subsequently migrate to the pancreatic tissue and instigate cellspecific death. That the retrovirus-encoded superantigen constitutes a candidate autoimmune gene is a novel idea, because it has the potential to be transmitted as either an inherited trait or an infectious agent. The next step in this quest will be to determine whether this superantigen is the direct cause of disease. There is an accumulation of circumstantial evidence for retroviral involvement in autoimmune disease: recently, retroviruses have been connected to multiple sclerosis [Perron , H.
422
MOL C
et al. (1997) Proc. Nat!. Acad. Sci. U. S. A. 94, 7583- 7588] and Sjogren's syndrome [Griffiths, D.J. et al. (1997) J. Virol. 71 , 2866-2877] . Exposure to retroviral superantigens as a triggering event in autoimmune phenomena is a compelling hypothesis that will , no doubt, lead to further investigations, focusing multidisciplinary approaches to study autoimmunity. Roger Hewson PhD Centre for Applied Microbiology and Research, Porton Down, Salisbury, Wiltshire, UK SP4 OJG .
Tangled triplets: intranuclear inclusions in Huntington's disease Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation Davies, SW et al. (1997)
LAR M E D I C I N E TODAY, O CTOB E R 1997
intranuclear inclusions containing both mutant protein and ubiquitin, increased nuclear indentations and increased number and clustering of nuclear pores. These changes preceded the development of neurologic abnormalities and were most prominent in cortex and striatum, the structures most affected by HD pathology. Similar changes have been described in biopsy specimens from HD patients. Scherzinger et al. expressed and purifed a series of fusion proteins of glutathione-S-transferase (GST) and the same portion of the huntingtin gene (exon 1) containing a polyglutamine expansion of 20-122 glutamines. In vitro , fusion peptides with larger polyglutamine segments formed insoluble complexes that resembled purified amyloid when examined by electron microscopy. Large insoluble proteins containing huntingtin epitopes were also detected in nuclear extracts of brain and, to a lesser ex1ent, liver from mice transgenic for exon 1 of huntingtin with 145 glutamines. These aggregates were not detected in the cy1osol or in nontransgenic littermates. Although neither of these studies prove that intranuclear inclusions or aggregates of abnormal huntingtin protein cause neuronal damage in HD, they raise the hypothesis that HD, and other CAG repeat disorders, might result from abnormal aggregation of normally Cy10plasmic proteins in the nuclei of affected neurons.
Cell 90, 537-548
Huntingtin-encoded polyglutamine expansions form amylOid-like protein aggregates in vitro and in vivo Scherzinger, E. et al. (1 997)
B. Joy Snider MD, PhD Instructor in Neurology, Dept of Neurology and Neurological Surgery, CSNSI, Washington University School of Medicine, Box 8111 , 660 S. Euclid Avenue, St Louis, MO 63110-1 093, USA.
Cell 90, 54~58 Huntington's disease (HD), dentatorubral and pallidoluysian atrophy and spinocerebellar ataxia (SCA 1, 2 and 3) are characterized by expanded segments of CAG trinucleotide repeats in the protein-coding regions of the affected genes. The CAG codons are translated into glutamines in the resulting proteins; how expansion of the repeat above a critical level (35-40 glutamines) causes disease in specific brain regions is still unknown, particularly as the genes are widely expressed outside the nervous system. Davies et al. generated a number of mouse lines transgenic for exon 1 of the human HD gene with 18- 156 CAG repeats . Mice with 115 or more repeats developed a neurodegenerative disorder reminiscent of human HD. Electron microscopic (EM) study of the brains of these mice showed prominent changes in neuronal nuclei, including opyright
The I8raIure page Is deeigned to alert readers to recant prinwy papers that . . important to biomedical reparticuB1r inncMdIve, likely to hIM IigIIIbnt cInIcaI impIct, or ccRnMrIIa A . . . d aeniar active re.aarcherlll COIIII1llllaued to aeIect one or two paperI paMahed k1 the last WIIkIIhit itwi*' their . . of ex...... If you .. Inanstad In Jc*1i1g
.'ardIn,
*
.................. ,.,..to the Mar at
1997 Ehevier cicncc LId. All righ ts rc,crvcd. 1357 - 43 10/97/$ 17.00