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Molecular analyses of Machado-Joseph disease

Machado-Joseph disease (MJD) is an inherited neurodegenerative disorder with an autosomal dominant inheritance. The brain regions affected by MJD include the Clarke column and spinocerebellar tracts, pons, dentate nuclei, substantia nigra, anterior horn cells, red nuclei, and peripheral nerves, but MJD is distinguished from other inherited cerebellar ataxias because it spares the olives and cerebellar cortex. The established phenotypes of MJD include gait and limb ataxia, ophthalmoplegia, dystonia, amyotrophy, dysarthria, rigidity, pyramidal signs, facial and lingual fasciculations, and bulging eyes (the most characteristic feature). In 1977 Romanul proposed the existence of a new disease entity based on apparent common clinical symptoms in four family pedigrees, including the Machado family and Joseph family (Nakano et al., 1972; Rosenberg et al., 1976). Since these pedigrees were all of Portuguese Azorean origin, the new disease was referred to as “Azorean disease” at the time (Romanul et al., 1997; Nakamoto et al., 1998). Later, the existence of several families with similar clinicopathological phenotypes of non-Azorean origin was reported, and therefore this disease has come to be more preferably known as Machado-Joseph disease (Healton et al., 1980; Lima and Coutinho, 1980; Sakai et al., 1983; Suite et al., 1986; Yuasa et al., 1986; Takiyama et al., 1989). In 1993, a linkage study of large Japanese pedigrees identified the MJD locus on a distal region of the long arm of chromosome 14 (Takiyama et al., 1993). Almost simultaneously, a locus covering a similar region on chromosome 14 was reported as the thirdly identified locus of spinocerebellar ataxia (Stevanin et al., 1994). In this review, we introduce our long-term studies of MJD, covering the identification of MJD1 (the gene responsible for MJD) to the recent molecular analysis of MJD, and from the data obtained from MJD analyses, we discuss the potential general molecular mechanisms that underlie a broad spectrum of neurodegenerative disorders, if not all of them.