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Clues to the causes of neurodegeneration
Literature
MOLECULAR MEDICINE TODAY, JUNE 2000 (VOL. 6)
Clues to the causes of neurodegeneration Neurodegeneration is a feature of a number of disorders, for example Alzheimer’s and Parkinson’s diseases, that have a significant impact on public health. Although there are a number of plausible hypotheses, the cause of neuronal death in these types of disorders is unknown. Lin and colleagues1 have identified early events that might result in neuronal death in the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1). SCA1 is an autosomal dominant disease in which the mutant protein apparently acquires a new, toxic function that results in cell death. Previous work on SCA1 mouse models has shown that nuclear localization of the mutant protein is essential to the development of SCA1-like symptoms. This requirement led Lin and colleagues to hypothesize that the mutant protein acts by altering transcription. Therefore, the group used a PCR-based cDNA subtractive-hybridization strategy to analyse gene expression in two mouse lines transgenic for SCA1 cDNAs with expanded glutamine tracts. It was found that one neuronal cDNA was upregulated, and six were downregulated, in both lines, relative to controls. Whereas the upregulation occurred at a later stage in disease development, the downregulation occurred very soon after transgene expression, well before any behavioural or pathological signs appeared, indicating that these changes happen very early in the disease process. The downregulated genes are involved in glutamate metabolism and calcium homeostasis, suggesting that alterations in these systems might be important in the subsequent neuronal death. There are, however, important questions that remain unanswered. For example, how does the mutant protein affect gene expression; do the changes lead to neuronal death (and if so, by what mechanism); does this scenario apply to other neurodegenerative disorders and, finally, can treatments aimed at preventing or ameliorating the effects of downregulation of these genes be developed?
Repetitive strain Many disease states, including developmental abnormalities and some cancers, are associated with characteristic chromosomal rearrangements, such as translocations and deletions. The recurrent nature of these karyotypic changes suggests that there are rearrangement hot spots, which have been assumed to consist of repetitive sequences. Sequence analysis of chromosome 22 provides insight into one such set of rearrangements1. The 22q11.2 deletion syndrome includes DiGeorge and velocardiofacial syndromes; most patients are hemizygous for a characteristic 3 Mb deletion, whereas others have smaller, nested deletions. There are four distinct low-copy repeats (LCRs) within this 3 Mb region – named A to D from centromere to telomere. These repeats have a modular structure consisting of smaller 40, 45 and 75 kb repeats combined in different numbers, orders and orientations in the four LCRs. Of 200 patients analysed by fluorescence in situ hybridization, 87% were found to have deletion endpoints in the two largest LCRs, A and D (350 and 250 kb, respectively). Subsequent rare-cutter restriction enzyme mapping of deletion patients without this A–D deletion identified A–B, A–C and C–D deletions. The localization of deletion endpoints within the LCRs is supportive of the involvement of repetitive regions in the deletion syndrome. Future studies aimed at sequencing the deletion breakpoints in the patients promise to shed light on the mechanisms underlying these deletions. Analysis of LCRs and their correlation with hot spots for chromosomal rearrangements should provide much medically relevant data. In view of the high level of similarity among LCRs – typically, 97–98% sequence identity between the modules reported here – it seems unlikely that LCRs will be resolved by the roughdraft sequence of the human genome due to be completed this year. Rather, LCRs are likely to confound the assembly of the genome sequence, and finished sequence, such as is available for chromosome 22, will be needed for their analysis. This further underlines the need for efforts to proceed to finish the genome after publication of the draft sequence. 1 Shaikh, T.H. et al. (1999) Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum. Mol. Genet. 9, 489–501 Robert A. Brooksbank PhD [email protected]
1 Lin, X. et al. (2000) Polyglutamine expansion downregulates specific neuronal genes before pathologic changes in SCA1. Nat. Neurosci. 3, 157–163 Kathryn L. Evans PhD [email protected]
1357-4310/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
Students... Did you know that you are entitled to a 50% discount on a subscription to Molecular Medicine Today ? See the bound-in subscription card for more details.
219
MOLECULAR MEDICINE TODAY, JUNE 2000 (VOL. 6)
Clues to the causes of neurodegeneration Neurodegeneration is a feature of a number of disorders, for example Alzheimer’s and Parkinson’s diseases, that have a significant impact on public health. Although there are a number of plausible hypotheses, the cause of neuronal death in these types of disorders is unknown. Lin and colleagues1 have identified early events that might result in neuronal death in the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1). SCA1 is an autosomal dominant disease in which the mutant protein apparently acquires a new, toxic function that results in cell death. Previous work on SCA1 mouse models has shown that nuclear localization of the mutant protein is essential to the development of SCA1-like symptoms. This requirement led Lin and colleagues to hypothesize that the mutant protein acts by altering transcription. Therefore, the group used a PCR-based cDNA subtractive-hybridization strategy to analyse gene expression in two mouse lines transgenic for SCA1 cDNAs with expanded glutamine tracts. It was found that one neuronal cDNA was upregulated, and six were downregulated, in both lines, relative to controls. Whereas the upregulation occurred at a later stage in disease development, the downregulation occurred very soon after transgene expression, well before any behavioural or pathological signs appeared, indicating that these changes happen very early in the disease process. The downregulated genes are involved in glutamate metabolism and calcium homeostasis, suggesting that alterations in these systems might be important in the subsequent neuronal death. There are, however, important questions that remain unanswered. For example, how does the mutant protein affect gene expression; do the changes lead to neuronal death (and if so, by what mechanism); does this scenario apply to other neurodegenerative disorders and, finally, can treatments aimed at preventing or ameliorating the effects of downregulation of these genes be developed?
Repetitive strain Many disease states, including developmental abnormalities and some cancers, are associated with characteristic chromosomal rearrangements, such as translocations and deletions. The recurrent nature of these karyotypic changes suggests that there are rearrangement hot spots, which have been assumed to consist of repetitive sequences. Sequence analysis of chromosome 22 provides insight into one such set of rearrangements1. The 22q11.2 deletion syndrome includes DiGeorge and velocardiofacial syndromes; most patients are hemizygous for a characteristic 3 Mb deletion, whereas others have smaller, nested deletions. There are four distinct low-copy repeats (LCRs) within this 3 Mb region – named A to D from centromere to telomere. These repeats have a modular structure consisting of smaller 40, 45 and 75 kb repeats combined in different numbers, orders and orientations in the four LCRs. Of 200 patients analysed by fluorescence in situ hybridization, 87% were found to have deletion endpoints in the two largest LCRs, A and D (350 and 250 kb, respectively). Subsequent rare-cutter restriction enzyme mapping of deletion patients without this A–D deletion identified A–B, A–C and C–D deletions. The localization of deletion endpoints within the LCRs is supportive of the involvement of repetitive regions in the deletion syndrome. Future studies aimed at sequencing the deletion breakpoints in the patients promise to shed light on the mechanisms underlying these deletions. Analysis of LCRs and their correlation with hot spots for chromosomal rearrangements should provide much medically relevant data. In view of the high level of similarity among LCRs – typically, 97–98% sequence identity between the modules reported here – it seems unlikely that LCRs will be resolved by the roughdraft sequence of the human genome due to be completed this year. Rather, LCRs are likely to confound the assembly of the genome sequence, and finished sequence, such as is available for chromosome 22, will be needed for their analysis. This further underlines the need for efforts to proceed to finish the genome after publication of the draft sequence. 1 Shaikh, T.H. et al. (1999) Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum. Mol. Genet. 9, 489–501 Robert A. Brooksbank PhD [email protected]
1 Lin, X. et al. (2000) Polyglutamine expansion downregulates specific neuronal genes before pathologic changes in SCA1. Nat. Neurosci. 3, 157–163 Kathryn L. Evans PhD [email protected]
1357-4310/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
Students... Did you know that you are entitled to a 50% discount on a subscription to Molecular Medicine Today ? See the bound-in subscription card for more details.
219