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Wide-reaching implications of recent research into GBA

Original article: Reduced sphingolipid hydrolase activities, substrate accumulation and ganglioside decline in Parkinson’s disease Molecular Neurodegeneration: 2019 

The takeaway

New research into the cellular clearance pathways governed by the GBA gene has shown reduced activity associated with both ageing and idiopathic Parkinson’s.

Why is it important?

These results shine a light on GBA-related dysfunction in Parkinson’s, with important implications for GBA mutations carriers as well as for the community on the whole. This work also highlights the importance of brain donation in furthering research to cure Parkinson’s.



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Impact Opinion

GBA-associated Parkinson’s has gradually become a distinct subtype of Parkinson’s, with clinical trials testing novel experimental therapies focused on boosting GCase activity (such as the Cure Parkinson’s Trust/Van Andel Institute supported Ambroxol study). This new paper not only provides further justification for evaluating GCase enhancing treatments, but also points towards specific biomarkers that could be explored as diagnostic aids or measures of conversion for individuals with RBD.


GBA is the gene that codes for GCase, a substance centrally involved in the clearance of waste products in the cell. Specifically, it is involved in handling certain glycosphingolipids (or GSLs – see additional PM summary link below for more information about this). The accumulation of GSLs inside the cell is detrimental to neurons. Previous work has shown that when these GSLs interact with alpha-synuclein, the protein which damages neurons in Parkinson’s, they render it especially harmful.

Although a very small number of people with Parkinson’s carry a mutation in the GBA gene, the current study asked whether dysfunction in GBA pathways may also be detected in those without the genetic mutation. In other words, could GBA-related cellular dysfunction feature centrally in idiopathic Parkinson’s?

The details

Collaborating research teams from Harvard, Imperial and Oxford analysed post-mortem samples of brain tissue donated to different Brain Banks by people with Parkinson’s and unaffected individuals. They also analysed cerebrospinal fluid (CSF), the fluid drawn by lumbar puncture, and blood samples, from another Parkinson’s group and unaffected controls, as well as people with REM sleep behaviour disorder (RBD). RBD can precede Parkinson’s by a number of years, so addressing GBA function in these individuals is also of interest.

The researchers found significant GCase activity reductions were associated with Parkinson’s but also with ageing, as its activity was lower in brain tissue samples from older individuals. They also found that compared to unaffected controls, there was a build-up of harmful GSLs, but also a reduction in specific gangliosides (which are complex GSLs essential for normal brain function) in the CSF and blood samples from people with Parkinson’s as well as RBD.

Next steps

As the results of the Ambroxol trial, which focuses specifically on the GBA pathway, are eagerly awaited, the current study highlights the possibility of focusing on gangliosides as a biomarker for Parkinson’s, as well as targeting GCase more generally as a therapeutic strategy.

Related work and trials

CPT Ambroxol trial

Where can I learn more?

Gene linked to inherited Parkinson’s identified

Discovering genetics of age at onset

Huebecker et al. (2019). Reduced sphingolipid hydrolase activities, substrate accumulation and ganglioside decline in Parkinson’s disease. Molecular Neurodegeneration, 14, 40.

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