GBA1: A mutated gene causes rapid ageing processes
For many years, medical doctors associated the GBA1 gene with a single disease: morbus Gaucher. This rare hereditary disease leads to a massive enlargement of spleen and liver and attacks the bone marrow, sometimes even destroying bones in the long term. Only gradually did researchers discover a completely new connection: parents and other relatives of Gaucher children develop Parkinson's disease at an above-average rate. Thanks to the latest methods of genetic analysis, scientists have now been able to systematically investigate the GBA1 gene in Parkinson's patients. The result: a mutation in the GBA1 gene is now considered the most frequent and most important genetic risk factor for the development of Parkinson's disease.
The underlying mechanisms are not known down to the last detail, but in simple terms they work as follows: The GBA1 gene contains the blueprint for the enzyme glucocerebrosidase. This enzyme is an important component of the body's own waste disposal system. It breaks down residual substances in the nerve cells, which are automatically formed in every person as a result of the natural processes in the cells. The older a person gets, the more residues accumulate, and if they are not broken down, they accumulate.
Most common genetic cause of Parkinson's disease
If there is a mutation in the GBA1 gene, it reduces the activity of the associated enzyme. As a result, the protein called alpha-synuclein is no longer broken down well enough in Parkinson's patients. Instead, a misfolding occurs; the protein is accumulated - and it is precisely this misfolded alpha-synuclein that triggers malfunctions in the nerve cells and ultimately even causes them to die.
A special phenomenon of GBA1 mutations is that they occur with a relevant frequency in people of all ethnic origins - this distinguishes them from mutations in other Parkinson's risk genes. This makes GBA1 the most common genetic factor in the development of Parkinson's, occurring in 5 to 15 per cent of all Parkinson's patients around the world. The fact that ‘mutations’ is in the plural is no coincidence: around 300 different mutations in GBA1 are currently known in research, each occurring in a different section of the gene. Their effects differ, which is why large Parkinson's centres not only analyse whether a GBA1 mutation is present for each patient, but also which one it is.
Parkinson's dementia as a hallmark of the GBA1 mutation
One of the special characteristics of Parkinson's is the heterogeneity of the disease: it can be caused by various triggers, each of which results in a different clinical progression. The GBA1 variant of Parkinson's is characterised by the fact that those affected are on average ten years younger than with the other Parkinson's variants. In addition, the disease usually progresses more quickly in them. The reduced degradation of alpha synuclein leads to a faster spread of this protein.
The GBA1 variant of Parkinson's is also characterised by the fact that patients develop Parkinson's dementia in most cases. This dementia differs significantly from Alzheimer's, for example, because patients do not forget who they are or where they live, but instead lose their flexibility: For example, they have difficulty completing several tasks at the same time.
GBA1 as a blueprint for metabolic processes
Parkinson's disease is only genetic in ten per cent of all cases - as is the case with patients from families with Gaucher's disease. The sporadic variant is far more common. However, the pathogenic metabolic pathways that take place in the nerve cells are similar in both cases. So what research is finding in patients with genetic disease is also prototypical for the sporadic variant. There is therefore hope that a drug could help many people affected.
Several studies are currently in preparation. One of them, entitled PreCoDe and involving the DZNE, aims to slow down or even prevent dementia in GBA1 patients.