Glucocerebrosidase mutations in Parkinson disease:molecular pathogenesis,and the basis for personalised therapy with small molecule chaperones

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease. Peak age of diagnosis is 62 years, but number of people with PD rises with age: 3100/100,000 >75 years and 4300/100,000 >85 years. The lifetime risk for PD in the UK is currently 3-4%.

At present, all treatment for PD is symptomatic, it does not slow down the progression of the disease. A drug that can slow or stop the disease is desperately needed.

There are many causes and factors that increase the risk of PD, but mutations of the GBA gene are the most important. Mutations of this gene increase the risk for PD by 20-30 times, and are found in at least 10% of PD cases.

Studies of brains from patients who have died with PD, cell models and animal models of GBA mutations and PD indicate that there is a close link between glucocerebrosidase enzyme GCase, the product of the GBA gene and alpha-synuclein (SNCA), the main protein involved in PD pathology. This relationship is reciprocal in that reduced GCase activity, for instance as a consequence of a mutation in the GBA gene, causes an increase in SNCA - such as is seen in PD. Alternatively, increased SNCA, for instance as a consequence of mutations in the SNCA gene, result in a reduction in GCase activity.

Importantly, we and others have shown in human cells and animal models that this relationship can be manipulated so that increasing GCase activity induces a reduction in SNCA levels. This is of considerable relevance to PD, and offers the opportunity to develop novel drugs to target this relationship and decrease SNCA levels and spread to slow or stop the progression of PD.

This project is designed to address important features of the GCase-SNCA relationship in preparation for clinical trials in this area in PD patients.


human studies animal studies
SMALL MOLECULE CHAPERONE increases GCase------which reduces SNCA
future human studies

In a pilot study we have used a drug currently available for use in patients for an entirely different illness and with a very good safety profile, in human cells from PD patients to show that it can increase GCase activity. This drug is a class known as a small molecule chaperone that interacts with GCase and increases activity of both the mutant and normal forms of this enzyme. Similarly our pilot studies have confirmed that this drug can reduce SNCA levels in neuronal cells.
Thus we are poised to enter the next stage towards developing this drug class for PD patients. Before we move to human studies we need to test the drug further in cell cultures from individuals with GBA mutations, with and without PD. The results will confirm the effect of small molecule chaperones to increase GCase activity. We will also be analysing how GBA mutations increase the risk of PD and how an individual's symptoms and signs can signal their risk for the disease. This will be very important in identifying those at risk and who would be best suited to receive a drug prior to the development of PD.
In addition, before moving to human studies we need to confirm the second part of the hypothesis equation above in an animal model. We need to confirm the effect of the drug on brain SNCA to reduce levels and potentially the spread of SNCA pathology.
If the results of the studies outlined here are positive, and our pilot data strongly indicate they will be, the next stage will be to move towards clinical trial in PD patients, and in parallel, to collaborate with industry to develop novel highly active small molecule chaperones for further testing and use in patients.

This application addresses the challenge of slowing the clinical and pathological progression of Parkinson disease (PD) with the use of small molecule chaperones to enhance the activity of glucocerebrosidase enzyme (GCase) activity in turn to reduce alpha-synuclein levels and retard neurodegeneration.

The programme will use a large cohort of >200 individuals with GBA mutations already recruited from the National Lysosomal Storage Disorders services at the Royal Free London and Addenbrokes hospitals. We propose to phenotype our expanded cohort for these parameters and to retest our complete group to identify progression of the abnormalities or conversion to clinically diagnostic PD.

The objectives of this Pathfinder grant are to:
1. Define the clinical evolution and phenotype of GBA mutation positive individuals as they progress to the development of PD. This will enable these features to be correlated with the underlying biochemical abnormalities.
2. Investigate the mechanisms of glucocerebrosidase enzyme (GCase) deficiency in patient derived primary (fibroblast) cultures obtained from our established cohort of GBA mutation positive individuals, age-matched non-GBA mutant PD patients and controls.
3. Determining the effect of small molecule chaperones to enhance GCase activity and reduce alpha-synuclein levels in patient cells and in animal models of human mutations to establish the validity of pursuing these as the next step as a therapy to slow progression in PD patients.

1. Pharmaceutical industry. Proof of principle of the action of small molecule chaperones in modulating alpha-synuclein levels will stimulate research in this area to use similar principles to influence protein levels in neurodegenerative dieases. This will initially be most applicable to Parkinson's disease, but will potentially impact on other neurodegenerative diseases.
2. Parkinson disease patients. Positive results from our project will naturally lead to clinical trials of a small molecule chaperone currently available for human use with a high safety profile. Again, if positive, this will lead to large clinical trials to test the hypothesis that the compounds slow disease progression in Parkinson disease.
3. Gaucher disease patients. GBA mutations in homozygous form cause Gaucher disease, a lysosomal storage disorder. Small molecule chaperones are under trial in this disease and positive results from our study will have important implications for patients with disease, and treatment would reduce their risk for Parkinson disease.
3. Interested beneficiaries will include the corresponding patient organisations i.e. Parkinson's UK, Michael J Fox Foundation, and Gaucher Disease Association.