Parkinson’s Gene Increases Risk of Dementia

One of the top Parkinson’s disease risk genes, glucocerebrosidase 1 (GBA1), appears to be an even bigger risk factor for the related synucleinopathy dementia with Lewy bodies (DLB), according to a report in the April 15 JAMA Neurology. Researchers led by Michael Nalls at the National Institute on Aging and Ellen Sidransky at the National Human Genome Research Institute, both in Bethesda, Maryland, analyzed almost 3,000 cases and controls. They concluded that GBA1 mutations confer an eightfold increased risk of DLB, as well as more than a sixfold increased risk of Parkinson’s disease with dementia (PDD). The results solidify the link between GBA, α-synuclein disorders, and dementia, and are likely to hone the interest of investigators and pharmaceutical companies in targeting the enzyme therapeutically.

“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

Comments

  1. This study confirms links between dementia with Lewy bodies (DLB) and glucocerebrosidase (GBA) mutations, expanding on several other studies that have shown links between GBA and Parkinson's disease (PD)/DLB. The strengths of this study are its multicentric nature and the large number of samples that greatly increase confidence. Besides this, consideration of the data leads to two other thoughts.

    A longstanding debate in the field is whether PD and DLB are distinct diseases, or fall within the same spectrum. Clinically, dementia is seen in about half of PD patients, and occasional Lewy bodies (LBs) in the neocortex are not uncommon in “PD”—as every neuropathologist knows. So my humble personal bias has been that, generally speaking, PD and DLB are diseases within the same spectrum, though there are exceptions and caveats to this rule. As is typical, evidence that could really change one’s mind comes from the quantitative realm of genetics. Specifically, studies such as this, showing GBA mutations in both PD and DLB, and also other studies showing that multiplications and mutations of α-synuclein can lead to either PD or DLB (1-3), support the view that there are common mechanistic threads between these two diseases and that they both fall within the same spectrum. What can these common mechanistic events be?

    An important clue comes from the knowledge that genetic multiplications of α-synuclein—even in rare sporadic cases (4)—lead to disease. Combined with the view that GBA mutations can decrease degradation of α-synuclein—effectively increasing its concentration within the cell—the collective evidence suggests common downstream mechanistic events that are secondary to elevated α-synuclein (protein) levels. As α-synuclein is a synaptic protein, we and others have proposed that such events occur at synapses first (5-8). Specifically, our data suggest that increased α-synuclein levels lead to decreases in neurotransmitter release, and this may relate to the normal function of this protein (5,6). A recent study looking at neurotransmission and dopaminergic neuronal pathology in an in-vivo α-synuclein overexpressing model shows early attenuations in exocytosis, supporting the “synaptocentric” view (9). Resolving various primary and secondary pathophysiologic links in these pathways is the next big challenge.

    References:

    Obi T, Nishioka K, Ross OA, Terada T, Yamazaki K, Sugiura A, Takanashi M, Mizoguchi K, Mori H, Mizuno Y, Hattori N. Clinicopathologic study of a SNCA gene duplication patient with Parkinson disease and dementia. Neurology. 2008 Jan 15;70(3):238-41. PubMed.

    Farrer M, Kachergus J, Forno L, Lincoln S, Wang DS, Hulihan M, Maraganore D, Gwinn-Hardy K, Wszolek Z, Dickson D, Langston JW. Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol. 2004 Feb;55(2):174-9. PubMed.

    Markopoulou K, Dickson DW, McComb RD, Wszolek ZK, Katechalidou L, Avery L, Stansbury MS, Chase BA. Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson's disease. Variability in familial Parkinson's disease. Acta Neuropathol. 2008 Jul;116(1):25-35. PubMed.

    Ross OA, Braithwaite AT, Skipper LM, Kachergus J, Hulihan MM, Middleton FA, Nishioka K, Fuchs J, Gasser T, Maraganore DM, Adler CH, Larvor L, Chartier-Harlin MC, Nilsson C, Langston JW, Gwinn K, Hattori N, Farrer MJ. Genomic investigation of alpha-synuclein multiplication and parkinsonism. Ann Neurol. 2008 Jun;63(6):743-50. PubMed.

    Scott DA, Tabarean I, Tang Y, Cartier A, Masliah E, Roy S. A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration. J Neurosci. 2010 Jun 16;30(24):8083-95. PubMed.

    Scott D, Roy S. α-Synuclein inhibits intersynaptic vesicle mobility and maintains recycling-pool homeostasis. J Neurosci. 2012 Jul 25;32(30):10129-35. PubMed.

    Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, Nicoll RA, Edwards RH. Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron. 2010 Jan 14;65(1):66-79. PubMed.

    Wu N, Joshi PR, Cepeda C, Masliah E, Levine MS. Alpha-synuclein overexpression in mice alters synaptic communication in the corticostriatal pathway. J Neurosci Res. 2010 Jun;88(8):1764-76. PubMed.

    Lundblad M, Decressac M, Mattsson B, Björklund A. Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons. Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3213-9. PubMed.

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References

News Citations

  1. More Than Gaucher’s—GBA Throws Its Weight Around Lewy Body Disease
  2. Feedback Loop—Molecular Mechanism for PD, Gaucher’s Connection
  3. Targeting α-Synuclein, Glucocerebrosidase May Work for LBD
  4. LRRK Watchers’ Eyes Turn to Inflammation, Autophagy, Kinase

Paper Citations

  1. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Dürr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009 Oct 22;361(17):1651-61. PubMed.
  2. Goker-Alpan O, Giasson BI, Eblan MJ, Nguyen J, Hurtig HI, Lee VM, Trojanowski JQ, Sidransky E. Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology. 2006 Sep 12;67(5):908-10. PubMed.
  3. Farrer MJ, Williams LN, Algom AA, Kachergus J, Hulihan MM, Ross OA, Rajput A, Papapetropoulos S, Mash DC, Dickson DW. Glucosidase-beta variations and Lewy body disorders. Parkinsonism Relat Disord. 2009 Jul;15(6):414-6. PubMed.
  4. Clark LN, Kartsaklis LA, Wolf Gilbert R, Dorado B, Ross BM, Kisselev S, Verbitsky M, Mejia-Santana H, Cote LJ, Andrews H, Vonsattel JP, Fahn S, Mayeux R, Honig LS, Marder K. Association of glucocerebrosidase mutations with dementia with lewy bodies. Arch Neurol. 2009 May;66(5):578-83. PubMed.
  5. Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, Buchman AS, Larson EB, Crane PK, Kaye JA, Kramer P, Woltjer R, Kukull W, Nelson PT, Jicha GA, Neltner JH, Galasko D, Masliah E, Trojanowski JQ, Schellenberg GD, Yearout D, Huston H, Fritts-Penniman A, Mata IF, Wan JY, Edwards KL, Montine TJ, Zabetian CP. GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology. Neurology. 2012 Nov 6;79(19):1944-50. PubMed.
  6. Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, Sidransky E, Grabowski GA, Krainc D. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011 Jul 8;146(1):37-52. Epub 2011 Jun 23 PubMed.
  7. Sardi SP, Clarke J, Kinnecom C, Tamsett TJ, Li L, Stanek LM, Passini MA, Grabowski GA, Schlossmacher MG, Sidman RL, Cheng SH, Shihabuddin LS. CNS expression of glucocerebrosidase corrects alpha-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy. Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):12101-6. Epub 2011 Jul 5 PubMed.

External Citations

  1. glucocerebrosidase 1
  2. National Gaucher Foundation
  3. LRRK2

Further Reading

Primary Papers

  1. 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;:1-9. PubMed.
  2. Klein C, Krainc D. Glucocerebrosidase Mutations: Tipping Point Toward Parkinson Disease and Dementia?. JAMA Neurol. 2013 Apr 15;:1-3. PubMed.

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