Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form

Trottier, Yvon; Devys, Didier; Imbert, Georges; Saudou, Frédéric; An, Isabelle; Lutz, Yves; Weber, C. R.; Agid, Yves; Hirsch, Étienne C.; Mandel, Jean‐Louis

doi:10.1038/ng0595-104

Cited by 411 publications

(239 citation statements)

References 38 publications

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“…51 Other studies have also concluded that both Huntingtin and HAP1 have a function in vesicular trafficking. [52][53][54] Of note is the fact that psychotic symptoms sometimes leading to a diagnosis of schizophrenia are found in Huntington's disease patients. 55,56 BBS4 and TTC8 are two members of the BBS family of proteins.…”

Section: Discussionmentioning

confidence: 99%

A threonine to isoleucine missense mutation in the pericentriolar material 1 gene is strongly associated with schizophrenia

et al. 2008

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Markers at the pericentriolar material 1 gene (PCM1) have shown genetic association with schizophrenia in both a University College London (UCL) and a USA-based case-control sample. In this paper we report a statistically significant replication of the PCM1 association in a large Scottish case-control sample from Aberdeen. Resequencing of the genomic DNA from research volunteers who had inherited haplotypes associated with schizophrenia showed a threonine to isoleucine missense mutation in exon 24 which was likely to change the structure and function of PCM1 (rs370429). This mutation was found only as a heterozygote in 98 schizophrenic research subjects and controls out of 2246 case and control research subjects. Among the 98 carriers of rs370429, 67 were affected with schizophrenia. The same alleles and haplotypes were associated with schizophrenia in both the London and Aberdeen samples. Another potential aetiological base pair change in PCM1 was rs445422, which altered a splice site signal. A further mutation, rs208747, was shown by electrophoretic mobility shift assays to create or destroy a promoter transcription factor site. Five further non-synonymous changes in exons were also found. Genotyping of the new variants discovered in the UCL case-control sample strengthened the evidence for allelic and haplotypic association (P = 0.02-0.0002). Given the number and identity of the haplotypes associated with schizophrenia, further aetiological base pair changes must exist within and around the PCM1 gene. PCM1 protein has been shown to interact directly with the disrupted-in-schizophrenia 1 (DISC1) protein, BardetBiedl syndrome 4, and Huntingtin-associated protein 1, and is important in neuronal cell growth. In a separate study we found that clozapine but not haloperidol downregulated PCM1 expression in the mouse brain. We hypothesize that mutant PCM1 may be responsible for causing a subtype of schizophrenia through abnormal cell division and abnormal regeneration in dividing cells in the central nervous system. This is supported by our previous finding of orbitofrontal volumetric deficits in PCM1-associated schizophrenia patients as opposed to temporal pole deficits in non-PCM1-associated schizophrenia patients. Caution needs to be exercised in interpreting the actual biological effects of the mutations we have found without further cell biology. However, the DNA changes we have found deserve widespread genotyping in multiple case-control populations.

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Section: Discussionmentioning

confidence: 99%

A threonine to isoleucine missense mutation in the pericentriolar material 1 gene is strongly associated with schizophrenia

et al. 2008

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“…Huntingtin is present in the cytoplasm, but not the nucleus or mitochondria of most cell types tested so far (Strong et al 1993 ;DiFiglia et al 1995 ;Gutekunst et al 1995 ;Trottier et al 1995 ;Wood et al 1996). The normal cellular function of this cytoplasmic protein remains unclear although an association with components of the cytoskeleton and synaptic vesicles in presynaptic nerve terminals suggest a role in intracellular transport (DiFiglia et al 1995 ;Gutekunst et al 1995).…”

Section:     '  mentioning

confidence: 99%

Of mice and men: solving the molecular mysteries of Huntington's disease

Shelbourne

2000

Journal of Anatomy

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Recent advances in the manipulation of mouse embryos provide opportunities for the disciplines of neuroscience and molecular genetics to join forces and tackle some previously intractable questions in this area of research. Even Huntington 's disease has started to yield clues to its complex pathophysiology as a result of the recent application of transgenic technologies. This short review, while necessarily providing some background clinical information on Huntington's disease, will focus on how modifications of the mouse genome have contributed, and are continuing to contribute, to our understanding of the complex disease process. Such new insights may well turn the hope of developing the first effective treatment for this devastating disease into reality.

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“…Huntingtin has been immunolocalized in a series of studies that have shown a strong cytoplasmic immunoreactivity (Trottier et al 1995;DiFiglia et al 1995;Gutekunst et al 1995;Sapp et al 1997), although there have been reports of nuclear localization (De Rooij et al 1996). However, the intranuclear inclusions have shown immunoreactivity associated only with epitopes in the furthermost N-teminal regions of huntingtin, the region within which the polyglutamine sequence resides Becher et al 1998).…”

Section: Introductionmentioning

confidence: 99%

The localization and interactions of huntingtin

1999

Phil. Trans. R. Soc. Lond. B

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Huntingtin was localized by using a series of antibodies that detected di¡erent areas of the protein from the immediate N-terminus to the C-terminal region of the protein. The more C-terminal antibodies gave a cytoplasmic localization in neurons of the brain in controls and cases of Huntington's disease (HD). The N-terminal antibody, however, gave a distinctive pattern of immunoreactivity in the HD brain, with marked staining of axon tracts and white matter and the detection of densely staining intranuclear inclusions. This implies some processing di¡erences between mutated and normal huntingtin. We have also localized two interacting proteins, cystathionine b-synthase and the nuclear receptor co-repressor (N-CoR), in brain. Cystathionine b-synthase was not relocalized in HD brain, but the N-CoR was excluded from neuronal nuclei in HD brain, and a further protein that exists in the same repression complex, mSin3, was similarly excluded. We conclude that the co-repressor might have a part in HD pathology.

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Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form

Cited by 411 publications

References 38 publications

A threonine to isoleucine missense mutation in the pericentriolar material 1 gene is strongly associated with schizophrenia

A threonine to isoleucine missense mutation in the pericentriolar material 1 gene is strongly associated with schizophrenia

Of mice and men: solving the molecular mysteries of Huntington's disease

The localization and interactions of huntingtin

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