Parkinson’s and waste removal
An important aspect to keep a cell healthy and functioning correctly is the breakdown and recycling of waste. This process is regulated by lysosomes; however, issues with them are common in neurons of people with Parkinson’s and may help drive cell loss.
What are lysosomes?
Lysosomes are like the refuse collectors of the cell – they handle the breakdown, disposal, and recycling of cellular waste. This includes things like excess proteins and dysfunctional or old cell structures. To achieve this, lysosomes are filled with specialised enzymes– proteins that catalyse (speed-up) chemical reactions. Lysosomes taxi these enzymes around the cell, breaking down waste as they go.
Issues with this waste disposal system are common in the nerve cells (neurons) of people with Parkinson’s and this is thought to contribute to cell loss. Problems that fall under this umbrella include issues with lysosomes, the enzymes they carry, and with transporting enzymes from where they are assembled to the lysosome. Researchers are currently looking at therapies that can address these problems, with the aim to increase neuron survival, therefore slowing Parkinson’s progression.
Why is waste removal important for Parkinson’s?
The removal of cellular waste is essential for a cell’s wellbeing. Problems with the lysosomes themselves is often seen in Parkinson’s, which can impact other drivers of Parkinson’s progression such as the accumulation of excess proteins and dysfunctional structures. More specifically, waste disposal problems can lead to the build-up of alpha-synuclein, as well as mitochondrial dysfunction.
Alpha-synuclein
Build-ups of dysfunctional copies of the protein alpha-synuclein are a hallmark and driver of Parkinson’s. This version of alpha-synuclein is sticky, clumping together to form Lewy bodies. Lewy bodies interfere with other cell processes, eventually leading to cell death if not cleared.
Learn more about alpha-synuclein and Parkinson’s.
Reduced lysosomal activity may contribute to neuron’s inability to mitigate these build-ups. Additionally, there is evidence to suggest that alpha-synuclein and Lewy bodies may interfere with the transport of enzymes to the lysosome, further reducing lysosomal activity.
Mitochondrial dysfunction
Mitochondria are like battery packs for the cell, creating and providing all the energy cells need to function. Over time, however, these mitochondria become less efficient and eventually need to be recycled in a process called mitophagy. Besides not being able to meet the energy demands of the cell, dysfunctional mitochondria can also lead to an overproduction of toxic molecules called reactive oxygen species, which in excess can trigger cell death.
Learn more about mitochondrial dysfunction.
Lysosomes are integral to this process as they are recruited to breakdown mitochondria. Therefore, reduced lysosomal activity or issues with recruiting these lysosomes may contribute to the accumulation of dysfunctional mitochondria.
How can genes play a role?
Genes are segments of our DNA (our genetic/hereditary information) that contain the instructions for building proteins and for directing cell activity. Mutations, or small changes in this genetic code, can muddy these instructions, leading to cells building less effective or dysfunctional proteins.
There are several genetic variations associated with a higher risk of developing Parkinson’s. The most common of these are variations to the GBA1 gene, which provides the instructions for building the lysosomal enzyme glucocerebrosidase (GCase). GCase activity is thought to decrease naturally with age but may be even lower in people with GBA1 mutations, affecting the cell’s ability to breakdown waste. Researchers believe therapies that increase GCase activity, such as ambroxol, could therefore have a protective effect on neurons.