Synonyms: Lysosomal glucocerebrosidase, acid β-glucosidase, GBA1, D-glucosyl-N-acylsphingosine glucohydrolase, GCase


Back to the Top

Homozygous mutations in the GBA gene cause Gaucher’s disease, the most common lysosomal storage disorder. GBA generated interest in the neurodegeneration field when clinicians observed parkinsonian symptoms in some patients with Gaucher’s—an autosomal recessive disease—and an increased incidence of Parkinson’s disease (PD) in their heterozygous older relatives. Subsequent studies in large samples of PD patients established GBA mutations as a genetic risk factor for PD, as well as for dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). Initially found in the Ashkenazi Jewish population, this was subsequently confirmed in other populations and in meta-analyses of PD samples worldwide. GBA currently ranks third in PDGene, after tau and α-synuclein. GBA mutations increase a person’s risk of PD, PDD, and DLB about fourfold. Upward of 5 percent of all patients with PD are estimated to have a GBA mutation; that number is higher in familial PD.

GBA is one of a growing number of genes that can cause a severe, early onset disease in homozygous carriers of a pathogenic mutation and a later-onset neurodegenerative disease in heterozygous carriers of the same mutation. Another example of this is TREM2.

Clinically, Gaucher’s disease occurs in three subtypes, one that affects the liver and spleen, bone, and blood, and two that also affect the central nervous system (see OMIM links below).  Parkinson’s disease linked to heterozygous GBA mutations is indistinguishable from sporadic PD clinically, pharmacologically, and in terms of drug response, although it begins earlier in life and is likelier to affect cognition, as well.

GBA encodes glucocerebrosidase, a lysosomal hydrolase that digests glycolipids. When the enzyme’s activity is impaired, these lipids build up in lysosomes, leading to cellular damage and inflammation. As PD, PDD, and DLB are diseases of α-synuclein aggregation, the link between GBA and α-synuclein is under intense study. A bi-directional pathway connecting GBA and α-synuclein has been implicated in the pathogenesis of both idiopathic and genetic forms of PD, PDD, and DLB. Pathogenic GBA mutations tend to cause loss of function and accumulation of the enzyme’s substrate glucosylceramide; this has been proposed to lead to a buildup and oligomerization of α-synuclein. In turn, high levels of α-synuclein interfere with the lysosomal function of wild-type glucocerebrosidase.

In animal models, reduced glucocerebrosidase function increases the accumulation of α-synuclein, whereas ramping up glucocerebrosidase expression ameliorates disease symptoms. Broadly speaking, protein quality-control pathways such as autophagy, the unfolded protein response, and endoplasmic reticulum-associated degradation have been implicated in the pathogenesis of both Gaucher’s and Parkinson’s.

Enzyme-replacement therapy with recombinant glucocerebrosidase is available for people with Gaucher’s. It does not cross the blood-brain barrier, hence it cannot treat the disease’s neurological symptoms, or PD, PDD, or DLB. The role of GBA in these diseases has renewed interest in the development of CNS-targeted therapies that boost glucocerebrosidase activity in the brain.


Alzpedia Citations

  1. Tau (MAPT)
  2. SNCA (α-synuclein)
  3. TREM2

External Citations

  1. PDGene

Further Reading


  1. . The link between the GBA gene and parkinsonism. Lancet Neurol. 2012 Nov;11(11):986-98. PubMed.
  2. . The association between mutations in the lysosomal protein glucocerebrosidase and parkinsonism. Mov Disord. 2009 Aug 15;24(11):1571-8. PubMed.
  3. . Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3537-42. PubMed.
  4. . α-Syn suppression reverses synaptic and memory defects in a mouse model of dementia with Lewy bodies. J Neurosci. 2011 Jul 6;31(27):10076-87. PubMed.
  5. . Glucocerebrosidase, a new player changing the old rules in Lewy body diseases. Biol Chem. 2013 Feb 22; PubMed.
  6. . 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.