Recently researchers have provided new insights into how small defects in a region of DNA called the GBA gene could be affecting cell biology and ultimately lead to the development of Parkinson’s.

Some of the most common genetic risk factors associated with Parkinson’s occur in an area of DNA called the GBA gene. The GBA gene makes an enzyme called glucocerebrosidase or GCase. GCase is active inside small structures called lysosomes, clearing waste from cells; and breaking down toxic substances, digesting bacteria that invade the cell, and recycling worn-out cell components. Individuals with Parkinson’s who carry a GBA mutation have very low levels of GCase function.

For some time researchers have been trying to determine why this loss in GCase activity could possibly be driving the development and progression of Parkinson’s. Now, a group of scientists led by Professor David Sulzer, who sits on our International Linked Clinical Trials committee, have published data demonstrating that it is not the reduction in GCase activity that may be causing problems, but rather an altered form of the GCase enzyme ending up in the wrong part of the cell.

When it is produced, GCase is transported to lysosomes; the lysosome then absorbs the GCase enzyme where it performs its job of waste processing. However, in cells that carry variants of the GBA gene, Prof. Sulzer and colleagues found that the altered form of the GCase enzyme is not absorbed into the lysosome, but rather sticks to the outside preventing other proteins from getting inside. These other proteins include alpha-synuclein which is known to form toxic accumulations in the brains of people with Parkinson’s. In Prof. Sulzer’s experiments, this accumulation of proteins caused stress to the cells, ultimately leading to the cells dying.

The results of this study are particularly interesting to Cure Parkinson’s as we have been repurposing a commonly used cough medication called ambroxol for Parkinson’s. This medicine has demonstrated the ability to increase GCase levels and improve lysosome function, and rescue cells with GBA mutations. Having exhibited encouraging results in a phase 2 clinical trial, we are now in the final stages of planning a large phase 3 trial to determine if ambroxol can slow the progression of Parkinson’s.