Ribosomal frameshifting on MJD-1 transcripts with long CAG tracts.

The expanded CAG tract diseases are a heterogeneous group of late-onset neurodegenerative disorders characterized by the accumulation of insoluble protein material and premature neuronal cell death. Recent work has provided support for several mechanisms that may account for neurodegeneration, but no unifying mechanism has emerged. We have previously demonstrated that in SCA3, the expanded CAG tract in the MJD-1 transcript is prone to frameshifting, which may lead to the production of polyalanine-containing proteins. To further examine the occurrence of frameshifting and understand its mechanism and possible role in pathogenesis, a cellular model was established. We show that this phenomenon results from ribosomal slippage to the -1 frame exclusively, that ribosomal frameshifting depends on the presence of long CAG tracts and that polyalanine-frameshifted proteins may enhance polyglutamine-associated toxicity, possibly contributing to pathogenesis. Finally, we present evidence that anisomycin, a ribosome-interacting drug that reduces -1 frameshifting, also reduces toxicity, suggesting a new therapeutic opportunity for these disorders.

Transgenic expression of an expanded (GCG)13 repeat PABPN1 leads to weakness and coordination defects in mice.

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder caused by a (GCG)n trinucleotide repeat expansion in the poly(A) binding protein nuclear-1 (PABPN1) gene, which in turn leads to an expanded polyalanine tract in the protein. We generated transgenic mice expressing either the wild type or the expanded form of human PABPN1, and transgenic animals with the expanded form showed clear signs of abnormal limb clasping, muscle weakness, coordination deficits, and peripheral nerves alterations. Analysis of mitotic and postmitotic tissues in those transgenic animals revealed ubiquitinated PABPN1-positive intranuclear inclusions (INIs) in neuronal cells. This latter observation led us to test and confirm the presence of similar INIs in postmortem brain sections from an OPMD patient. Our results indicate that expanded PABPN1, presumably via the toxic effects of its polyalanine tract, can lead to inclusion formation and neurodegeneration in both the mouse and the human.

A novel locus for pure recessive hereditary spastic paraplegia maps to 10q22.1-10q24.1.

The hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders characterized by progressive lower-limb spasticity. In this study, we performed linkage analysis on an autosomal recessive pure HSP family and mapped the disease to chromosome 10q22.1-10q24.1, a locus partially overlapping the existing SPG9 locus. We have either identified a novel locus for pure recessive HSP (SPG27), or we have found the first case of allelic disorders with different mode of inheritance in HSP. If the disorders are indeed allelic, our results have reduced the SPG9 interval by 3Mb with D10S536 and D10S1758 as flanking markers.

Molecular cloning and characterization of human RAI1, a gene associated with schizophrenia.

Schizophrenia is a common neuropsychiatric disorder of uncertain etiology that is believed to result from the interaction of environmental factors and multiple genes. To identify new genes predisposing to schizophrenia, numerous groups have focused on CAG-repeat-containing genes. We previously reported a CAG repeat polymorphism that was shown to be associated with both the severity of the phenotype and the response to medication in schizophrenic patients. In this article, we now report the genomic structure of this gene, the retinoic acid inducible-1 gene (RAI1), and present its characterization. This gene, located on chromosome 17p11.2, comprises six exons coding for a 7.6-kb mRNA. The RAI1 gene is highly homologous to its mouse counterpart and it is expressed at high levels mainly in neuronal tissues.