“This confirms what was suspected for a long time. These mutations are important for dementia in PD and DLB,” Pablo Sardi at Genzyme Corporation, Framingham, Massachusetts, told Alzforum. Robert Edwards at the University of California, San Francisco, agreed, writing to Alzforum, “The work suggests a prominent role for cognitive dysfunction in synucleinopathies.”

Homozygous mutations in GBA1 cause Gaucher’s disease, a lysosomal storage disorder marked by the accumulation of the lipid glucocerebroside in cells throughout the body. People with Gaucher’s can exhibit parkinsonism and neurological problems, and their relatives often develop PD, suggesting a connection between the disorders. In 2009, mutations in GBA1 were linked to PD in several studies (see ARF related news story). The largest was a multicenter analysis of more than 5,600 patients with PD, performed by Sidransky and colleagues. They found that GBA1 mutations increased Parkinson’s risk 6.5-fold. In addition, carriers developed the disease an average of four years earlier and had more cognitive problems than did non-carriers (see Sidransky et al., 2009). Smaller studies of DLB patients consistently showed a link to GBA1 mutations as well, but produced widely varying estimates of effect size (see Goker-Alpan et al., 2006; Farrer et al., 2009; Clark et al., 2009; and Tsuang et al., 2012).

To come up with a more reliable estimate for DLB risk, Sidransky and colleagues performed a meta-analysis, pooling data from 11 centers in North America, Europe, and Australia. They compared 721 people with DLB and 151 people with PDD to almost 2,000 controls matched for age, sex, and ethnicity. GBA1 mutations were not only 8.3 times more common in people with DLB, but were also associated with more severe symptoms and earlier disease onset (by about five years). For PDD, the odds ratio was 6.5, similar to that found for PD. Since methods varied widely among centers, the authors also performed subgroup analyses, stratifying by factors such as different methods of genotyping. Most of these analyses produced even higher odds ratios for GBA mutations in DLB, up to 14.2. “Overall, I’m happy with the relative consistency of the results,” first author Nalls told Alzforum. He noted that in genetics, any odds ratio above 5 indicates quite substantial risk.

Only about 8 percent of people with DLB have a GBA1 mutation. However, growing evidence suggests that GBA may play a central role in the development of synucleinopathies even in people without a mutation. High levels of α-synuclein interfere with trafficking of wild-type GBA, thus preventing the enzyme from doing its job. Low GBA activity, in turn, leads to the accumulation of its substrate glucosylceramide, which seems to stabilize toxic α-synuclein oligomers (see ARF related news story on Mazzulli et al., 2011).

“The bidirectional effects of [α-synuclein] and GBA form a positive feedback loop that, after a threshold, leads to self-propagating disease,” wrote Christine Klein at the University of Lübeck, Germany, and Dimitri Krainc at Massachusetts General Hospital, Boston, in an accompanying editorial. The findings “suggest a general role for this pathway in idiopathic PD and now also other synucleinopathies, including DLB and PDD,” they wrote.

Further strengthening GBA’s role in synuclein diseases and dementia, researchers led by Sardi showed that injecting recombinant GBA into the hippocampus of young Gaucher’s disease model mice lowered α-synuclein levels and improved memory (see ARF related news story on Sardi et al., 2011). Altogether, these studies point to GBA as a promising therapeutic target for synucleinopathies, said Brian Spencer at the University of California, San Diego. One hurdle is that Cerezyme™, a recombinant GBA enzyme made by Genzyme and used to treat people with Gaucher’s disease, does not cross the blood-brain barrier. Gaucher’s disease affects only about one in 20,000 people, according to the National Gaucher Foundation. Now that the disease has been linked to PD and DLB, which have much larger patient populations, it may become more attractive for pharmaceutical companies to pour resources into developing a drug that enters the brain, Spencer suggested.

Sardi agreed, noting, “A lot of interest from industry has been building in the last three years.” GBA is attractive in part because it offers a clear and familiar pathway. “We have 30 years of experience using Cerezyme in humans,” Sardi pointed out. This contrasts with other common PD-associated mutations such as LRRK2, where little is known about the disease mechanism or how to target it, Sardi said (see ARF related news story). Drug development programs targeting brain GBA are still in the early preclinical phase, with no immediate plans for human trials, he added.––Madolyn Bowman Rogers.

References:
Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, Chinnery PF, Morris CM, Theuns J, Crosiers D, Cras P, Engelborghs S, De Deyn PP, Van Broeckhoven C, Mann DM, Snowden J, Pickering-Brown S, Halliwell N, Davidson Y, Gibbons L, Harris J, Sheerin UM, Bras J, Hardy J, Clark L, Marder K, Honig LS, Berg D, Maetzler W, Brockmann K, Gasser T, Novellino F, Quattrone A, Annesi G, De Marco EV, Rogaeva E, Masellis M, Black SE, Bilbao JM, Foroud T, Ghetti B, Nichols WC, Pankratz N, Halliday G, Lesage S, Klebe S, Durr A, Duyckaerts C, Brice A, Giasson BI, Trojanowski JQ, Hurtig HI, Tayebi N, Landazabal C, Knight MA, Keller M, Singleton AB, Wolfsberg TG, Sidransky E. A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol. 2013 Apr 15. Abstract

Klein C, Krainc D. Glucocerebrosidase mutations: Tipping point toward Parkinson disease and dementia? JAMA Neurol. 2013 Apr 15. Abstract