Progress and Prospects in Parkinson's Research/Causes/Inheritance/GBA

The GBA gene has been implicated in the onset of some types of familial Parkinson’s Disease.

General Data

Its official Full Name is “Glucosidase Beta Acid”.

Like many other genes GBA is known by more than one name.

Alternative names are:-

• GCB
• GBA1
• GLUC

In the human genome it is to be found on the long arm of chromosome 1.

The cytogenetic location is 1q22

The molecular base pairs are from 155,204,238 to 155,214,632

The PD Gene database (2011) lists 2 Polymorphisms for this gene both of which are termed ‘Significant’. It also cites 27 Caucasian gene association studies, 5 Asian studies, 9 Other/Mixed studies and 1 Caucasian Family-based study.

What does GBA do?

In a healthy brain GBA codes for production of a lysosomal enzyme that breaks down glucocerebrosidase, a potentially harmful fatty substance normally found in the body, into a sugar (glucose) and a simple fat molecule (ceramide). The expressed protein is 515 amino acids long.

What is the effect of mutations?

Mutations of the GBA gene are inextricably associated with Gaucher's Disease. Reference to GBA in the On-line Mendelian Inheritance in Man database produces considerable data on Gaucher’s with incidental references to Parkinsonism. There are three types of Gaucher’s and Type 3 is the one which is more commonly associated with neurological dysfunction.

This variant of Parkinson’s Disease could therefore be viewed as a subset of Type 3 Gaucher’s and differs from other forms of Parkinson’s Disease in a number of ways:-

• The onset is earlier. GBA-PD manifests itself at an average age of 41.

• It is recessive. Both parents have to have the same polymorphism before the mutation can express itself. Carriers of a single version of the defect are unaffected and the disease can skip generations.

• Patients do not accumulate clumps of the protein alpha synuclein (Lewy bodies) in their dopaminergic neurons and instead have an excess of glucocerebrosidase.

• It is particularly prevalent among people whose pedigree is descended from Ashkenazi Jews.

The faulty gene thus allows accumulation of glucocerebrosidase, which can harm the spleen, liver, lungs, bone marrow and the brain. Over 300 potentially harmful polymorphisms of the GBA gene have been identified. Two which have been linked to Parkinson’s Disease are GBA_N370S and rs2230288.

Research

Sidransky et al (2009) described a link between PD and GBA. Its publication produced the following observations from Adam S. Bristol 29.11.2009.:-

“I'm somewhat surprised that this paper has not received more attention than it has ... the study was indeed a tour de force in that it coordinated a risk analysis of GBA mutations in over 10,000 subjects across 16 research centers worldwide. A major challenge in a study of this type is coordinating and standardizing the data collection. This issue is particularly relevant here as nearly 300 GBA mutations of different types (e.g. missense, point mutations, etc.) have been identified to date; ideally, one would like measure the combined frequency of all GBA mutations and the risk of PD. Of course, how PD is diagnosed can vary too, so the analysis is not trivial.

The take-home messages for me were as follows:-

• While the data sets were "incomplete" in the sense that not all subjects had full GBA exon sequencing to identify all mutations nor did they get a full work-up for a complete clinical data set, the inclusion of so many patients across multiple ethnicities and geographies lends a robustness to the findings that previous studies of GBA lacked.

• GBA mutations were associated with earlier onset of PD, family history of PD, and higher incidence of non-motor symptoms, but lower incidence of bradykinesia and resting tremor.

• These relationships are probably underestimated because of the incomplete genetic and phenotypic data available. That is, if samples from all patients had been fully sequenced, other rarer mutations would likely have been found.

• Intriguingly, the odds ratio, or the strength of the associations, varied quite significantly across patient cohorts. What other co-factors might account for this?

This study has clear implications for genetic counselling, but my mind leaps immediately to therapeutics. Might this finding lead to a new treatment approach? Sidransky et al. argue that GBA is a susceptibility factor and not a cause of PD, but even so, might targeting GBA in PD patients with identified GBA mutations be included in the overall treatment regime? It's too early to tell, but here is some food for thought.

As readers may know, glucocerebrosidase (GBA) is a lysosome enzyme which, when deficient due to mutations, results in Gaucher's disease. The N370S and L444P mutations included in the Sidransky et al. study are involved in Gaucher's disease, a lysosomal storage disease that presents with neurological signs among others. Indeed, parkinsonian symptoms have been observed in Gaucher's patients and the relatives of Gaucher's disease patients have been observed to have a higher incidence of PD. Gaucher's disease patients are typically treated (quite successfully) with an intravenous enzyme replacement therapy. Given the current understanding of GBA and PD, this treatment is not practical or advisable for PD patients. An orally-delivered small molecule that targets GBA might be a possibility if the safety profile is sufficient and it doesn't adversely affect current standard of care. Amicus Therapeutics is developing a compound that hits and "re-activates" the N370S mutated GBA.”</blockquote.>

Horowitz et al (2011) identified a further PD-related mutation at E326K.

Where do we go from here?

Bianco and Bjorklund (2009) have developed a mouse model of a GBA-PD mutation and are testing this against a series of environmental ‘triggers’ to see which are likely to invoke the disease.

Bonkowsy (2010) is developing a zebra fish model of a GBA-PD mutation and using it to test how GBA might combine with other genes to invoke the disease.

Theoretically GBA cases of PD could be eliminated in future by identifying carriers of single copies of the mutant genes and counselling them not to mate with other like carriers!

Further reading

OMIM entry

GBA Genetics Home Reference

HuGENet Case Study

Today

Use the following links to query the PubMed, PubMed Central and Google Scholar databases using the Search terms:- Parkinson's_Disease GBA.

This will list the latest papers on this topic. You are invited to update this page to reflect such recent results, pointing out their significance.

Pubmed (abstracts)

Pubmed_Central (Full_Text)

Google_Scholar

Related Pages

Causes > Inheritance

Sub Pages:

SNCA - LRRK2 - MAPT - GBA - HLA