9 June 2009. This news story on the glucocerebrosidase (GBA) gene closes the Alzforum series on emerging concepts in the neurodegenerative disease spectrum. This latest genetics discovery may help scientists distinguish cases on the Lewy body end of the spectrum (i.e., toward Parkinson disease and some dementia with Lewy bodies) from the plaque and tangle end of the spectrum (i.e., Alzheimer disease). This year alone has seen five original research papers and several reviews on the growing realization that heterozygous mutations and pathogenic alleles of this enzyme are the most prevalent risk factor known to date for PD and other Lewy body diseases. “This is a big story,” said John Hardy, who argued at recent conferences that the GBA gene deserves a central place in the genetic lineup of Lewy body disease genes (see Part 8). These days, GBA ranks first on the Top PDGene Results, though these rankings change constantly with additional findings. Even since that database was last updated, a torrent of new data on larger patient groups and a greater number of rare disease variants appeared online this month. It further solidifies the position of the Gaucher disease gene as a major risk gene for sporadic and even familial clustering of these diseases. “We can have confidence that GBA has an important role in the pathogenesis of Lewy body disorders,” wrote James Leverenz of University of Washington, Seattle, and colleagues in an editorial accompanying the latest two papers in Archives of Neurology (Leverenz et al., 2009).

Until recently, GBA was known primarily for causing Gaucher disease. This is an autosomal recessive, lysosomal storage disease of glucocerebrosidase deficiency. It can cause acute liver damage even early in life, typically in homozygous mutation carriers, when the substrate of the mutated, sluggish enzyme—the lipid glucocerebroside—accumulates in cells. At some 10,000 estimated cases worldwide, Gaucher’s is an orphan disease. The gradual expansion of GBA’s relevance to a much larger group of people historically began with case reports of parkinsonism in Ashkenazi Jewish patients with Gaucher disease (Neudorfer et al., 1996; Machaczka et al., 1999). These reports initially drew little attention among PD epidemiologists and geneticists, said Hardy. More widely noted, at least in the U.S., were papers by Ellen Sidransky at the NIH in Bethesda, Maryland, who pursued her clinical observation that fathers and uncles of her patients with Gaucher’s tended to show parkinsonian symptoms. Sidransky’s group conducted a series of small studies looking at neuropathology and GBA mutations in family members (Tayebi et al., 2001; Wong et al., 2004; Tayebi et al., 2003; Lwin et al., 2004).

Together, the Israeli and U.S. work inspired groups worldwide to look for GBA mutations in PD patient series of non-Ashkenazi origin. These studies were generally small and only assessed specific GBA SNPs known from Gaucher disease, not the entire sequence of the gene, but even so, many of them were positive. Overall, this existing work led to a sense that the acute liver problems of Gaucher’s develop when a person lacks at least 80 percent of GBA activity, whereas milder, or the more common heterozygous mutations that eliminate about half of the body’s GBA activity enable a healthy childhood but can cause later-onset Lewy body diseases such as PD or dementia with Lewy bodies, Hardy and colleagues write in a review out this month (Hardy et al., 2009).

In the past three months, the story suddenly bulked up when data on larger patient series pouring in. In Prague, Laura Parkkinen of University College London, UK, presented that group’s latest results on 790 patients with PD and 257 controls. Four percent of the patients had one of 14 different GBA mutations, adding up to a total odds ratio of 3.7. All GBA carriers who had consented to autopsy showed extensive Lewy body pathology in their brain. Clinically, about half had typical PD; the other half also had the hallucinations and cognitive decline that marks dementia with Lewy bodies (DLB, see part 3 of this series). “GBA mutations are the most common genetic risk factor for developing sporadic PD or DLB in this large British population,” Parkkinen said. This data appeared last March (Neumann et al., 2009), as did the results of a separate series of 172 Greek Parkinson’s patients in whom GBA also proved the most commonly mutated gene, amounting to a similar odds ratio of 4.2 (Kalinderi et al., 2009).

Still-larger datasets rolled in this month from Japan and New York. Led by Shoji Tsuji at University of Tokyo Graduate School of Medicine, first author Jun Mitsui and collaborators at other Japanese institutions reported that their re-sequencing effort of the entire GBA gene in 534 PD patients and 544 controls discovered 11 pathogenic variants that together occurred in a total of 10 percent of patients but in almost no controls, leading to a whopping odds ratio of 28 (Mitsui et al., 2009). The British, the Greek, and the Japanese studies, as had some previous ones, all found that GBA mutations showed up particularly in early-onset patients. The large patient group in the Japanese sample included 34 families with clusters of PD cases; of those families, eight had heterozygous GBA variants that showed up in all affected relatives, making GBA a gene not only for sporadic PD, but also for some forms of autosomal-recessive familial PD.

These data imply that the field will have to abandon the comparatively simple idea that common diseases like PD are caused by common gene variants. Instead geneticists are coming to grips with the more complex notion that common diseases are caused by many different variants, many of which will be rare. “We should emphasize a paradigm shift from the common disease—common variants hypothesis to the common disease—multiple rare variants hypothesis in our search for disease susceptibility genes in sporadic PD, which may be applicable to studies of other diseases,” Mitsui and colleagues wrote. In practice, this paradigm shift amounts to a tall order, as finding these multiple rare variants requires extensive sequencing of the entire gene in cases as well as in many controls. For GBA, this is difficult because the existence of an adjacent pseudogene makes this whole genomic region challenging to dissect.

For its part, the New York City study, led by Karen Marder at Columbia University, focused on patients with dementia with Lewy bodies (DLB). Of 95 people who had pathologically confirmed Lewy body disease, fully 28 percent had GBA mutations. Relatively fewer, that is, 10 percent, of people who had AD pathology also had GBA mutations, as did 3 percent of controls without either AD or Lewy body pathology. These authors report that in their patient sample, GBA mutations tended to lead to extensive α-synuclein pathology in the cortex. They suggest that in this way, GBA might serve as a diagnostic marker during life, indicating that mutation carriers likely have “purer” Lewy body pathology and that their dementia results primarily from that, not from the amyloid and tau pathology that marks AD (Clark et al., 2009).

How GBA variants cause PD and DLB is unknown at this point, because the molecular work studying the variants remains to be done. However, in these early days, most scientists interviewed for this article leaned toward a loss-of function mechanism. Some scientists noted that research into whether glucocerebrosidase variants might impair protein degradation in lysosomes might lead to new insights about α-synuclein processing and aggregation. Others raised the notion that GBA enzyme activity could provide a basis for developing fluid biomarkers (e.g., Balducci et al., 2007), similarly to the way they are coming along for progranulin, a growth factor whose own loss of function is genetically linked to many cases of frontotemporal dementia (see Part 7). That is in the future; but even now, scientists agree that recent genetics news have noticeably shifted the PD and DLB landscape toward lysosomal ceramide metabolism as a promising area of research (see series Part 8; also Depaolo et al., 2009).—Gabrielle Strobel.

This is Part 9 of a nine-part series. See also Part 1, Part 2, Part 3, Part 4, Part 5, Part 6, Part 7, Part 8.