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Nature Scientific Reports links glucocerebrosidase (GCase) dysfunction and neurodegenerative diseases


Mathias Alder 300x169

“The published data propose that strategies to alleviate dysfunction such as
targeting GCase could be a new therapeutic opportunity
for neurodegenerative diseases and lysosomal storage disorders.” 

 Matthias Alder, CEO, Gain Therapeutics


In recent weeks, our collaborators with the Institute for Research in Biomedicine and the NeuroCenter of Southern Switzerland of EOC published new data in Nature Scientific Reports ( In this important publication, researchers showed novel mechanisms linking glucocerebrosidase (GCase) dysfunction, lysosomal dysfunction and Tau accumulation to neurodegenerative diseases. The findings provide further scientific validation of therapeutic approaches that address GCase and lysosomal dysfunction for Parkinson’s and other neurodegenerative conditions.

Neurodegenerative disorders are characterized by the brain deposition of insoluble amyloidogenic proteins, such as α-synuclein or Tau, and the concomitant deterioration of cell functions such as the autophagy-lysosomal pathway (ALP). Heterozygous mutations of several ALP genes represent risk factors for Parkinson’s disease. The objective of the research was to try to elucidate the role of lysosomes during Tau accumulation using human derived samples and cells. The researchers found that Tau can accumulate in degradative organelles leading to a lysosomal stress that in turn enhances Tau accumulation. Furthermore, reduction of glucocerebrosidase activity, which is a hallmark in Gaucher’s disease and a main genetic risk factor for Parkinson’s disease, causes lysosomal dysfunction in primary fibroblasts and contributes to the accumulation of Tau. Considering the presence of Tau lesions in Parkinson’s disease as well as in multiple neurodegenerative disorders including Alzheimer’s disease, the published data would suggest that strategies to alleviate ALP dysfunction could be a new therapeutic opportunity for neurodegenerative diseases and other lysosomal disorders.

One such strategy of alleviating ALP-dysfunction would be through the targeting of the GCase enzyme. Rescuing GCase functionality may be a therapeutic avenue to limit the accumulation and misfolding of tau in neurodegenerative disease sequelae. Gain’s lead candidate GT-02287, that has shown the ability to modify GCase functionality could demonstrate a direct therapeutic intervention that can alleviate lysosomal stress by allowing GCase to properly metabolize accumulated proteins. In the case of tau, breaking down accumulated isoforms can limit its aggregation and the associated cellular dysfunction. In addition, it limits misfolded tau’s ability spread outside of the affected cell. This provides further validation for Gain’s fundamental approach with GT-02287 – by stabilizing and increasing GCase function, lysosomal health improves, which has the potential for a significant therapeutic improvement not just for Parkinson’s disease but for other forms of neurodegenerative disorders.



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