New Insights Into Parkinson's Disease

New research on fruit flies is suggesting Parkinson's disease arises from endoplasmic reticulum stress, not mitochondrial dysfunction

Parkinson's disease is currently poorly understood, but it is primarily characterised by the death of dopamine neurons in the substantia nigra (visible above in red). Familial versions of the disease appear to centre around malfunctioning mitochondria, the batteries of the cell. However, new information is hinting that issues with the endoplasmic reticulum, an organelle involved with protein folding, may actually be more important. 

New findings in fruit flies

Fruit flies might not seem like a good model of human disease, but 75% of human disease causing genes are present in a similar form in flies. Model organisms have actually proved great predictive models of human disease, and help to identify similar candidates in humans. 

The endoplasmic reticulum, shown in pink, is a maze like structure responsible for producing and folding proteins correctly

In pursuit of greater understanding, a team of researchers analysed a group of fruit flies with mutations in genes called pink1 or parkin. Both of these appear to prevent faulty mitochondria being disposed of correctly, and both are implicated in familial Parkinson's disease. Flies with mutations in either exhibit a similar loss of dopaminergic neurons and lose the ability to fly correctly.

A link to the endoplasmic reticulum (ER)

Pink1 and parkin mutant flies showed increased amounts of ER stress, meaning that they were manufacturing proteins at a reduced rate. Levels of a molecule called BiP were also high, which is an indicator of ER stress. Both genes assist in degrading a protein called mitofuscin, which binds the ER to mitochondria like an anchor. Curiously, mutant flies showed greater numbers of ER attached mitochondria than normal flies. The researchers hypothesised that this increased, sticky tethering was preventing damaged mitochondria from being destroyed. 

Credit: University of Leicester

Furthermore, when the scientists decreased levels of mitofuscin, the number of neurons actually increased. This has a protective effect on the flies' muscle function too, despite an increased number of dysfunctional mitochondria. Reducing mitofuscin levels and ameliorating ER stress was able to effectively protect against neurodegeneration. 

 "This research challenges the current held belief the Parkinson's disease is a result of malfunctioning mitochondria. By identifying and preventing ER stress in a model of the disease it was possible for us to prevent neurodegeneration. Lab experiments, like this, allow us to see what effect ER stress has on Parkinson's disease. While the finding so far only applies to fruit flies, we believe further research could find that a similar intervention in people might help treat certain forms of Parkinson's"

Find out more about the research in this video:

Celardo et al. "Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease" Cell Death and Disease (2016). 

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