I have talked a lot about Alzheimer’s Disease and how we think it progresses as a neurodegenerative disease etc. This time I’m going to talk about another neurodegenerative disease – Parkinson’s disease. Like in Alzheimer’s, Parkinson’s Disease has worsening symptoms as it progresses because of increasing levels of neuronal damage. It is mainly a motor disorder where control over movement is lost.
Parkinson’s is also caused by the build-up of a misfolded protein called α-synuclein. This protein can stick (or aggregate) together to form build-ups called Lewy Bodies. In Alzheimer’s, Tau and amyloid β first build up in the hippocampus, causing memory loss. In a similar way, Lewy Bodies form in the substantia nigra, where they destroy dopamine signalling neurones required for controlling movement.
That’s a brief overview of Parkinson’s disease (aren’t my blog posts up beat?!), but what I really want to talk to you about is an interesting link between these two neurodegenerative diseases. In a surprising number of dementia cases, signs that are normally associated with Parkinson’s disease have been found. The presence of α-synuclein appears to occur alongside tau. Not only this, but it appears that the two proteins somehow interact to cause a more severe form of the disease. Structures in the brain are damaged more when both of the misfolded proteins are present. But, as per usual, this is about all that is known. There are some theories about how α-synuclein causes an increase in tau’s affects:
Tau normally helps to ‘stabilise’ structures called microtubules in our neurones. These microtubules act like trains to transport goods from one end of the cell to the other. In Alzheimer’s, the tau can no longer do this because of modifications to its structure, in part caused by a particular enzyme. A possible theory is that when α-synuclein is present, it activates this enzyme into further modifying tau, causing the ‘trains’ in our cells to stop transporting. As you might expect, if proteins aren’t reaching the areas of the cell where they are needed, there is going to be a nasty knock-on effect on how the neurone will function.
A project in our lab has recently shown that over-expressing both tau and α-synuclein in flies (poor flies) causes a larger change in the animal’s behaviour. Casey Morris, a PhD student in our lab, spent her undergrad project creating genetically modified cell lines expressing both Alzheimer’s related and Parkinson’s related proteins. The flies were put through all sorts of experiments to determine changes in their behaviour. Over 3 months, she monitored the flies and was able to calculate any differences in their average life span. She found that when both tau and α-synuclein were expressed in the brain, the life span of the flies was significantly decreased compared to when just tau was expressed. She also used a technique to monitor the climbing ability of the flies. If you tap a fly to the bottom of a tube, it pretty quickly runs back up. With age and in disease, this climbing ability decreases. When the two proteins acted together, the fly’s climbing ability decreased at a faster rate than with just tau alone.
These simple behavioural studies prove that when the protein normally associated with Parkinson’s disease is also present in the brain of someone with Alzheimer’s Disease (or some tested animals at least), causes more dramatic effects.
Parkinson’s like symptoms have been linked to Alzheimer’s disease and this mixed bunch of disrupted protein might provide a reason why. There has also been some cases where tau has accumulated in the neurons affected in Parkinson’s disease (in the substantia nigra), possibly another reason for the overlapping symptoms.
More work is needed to determine exactly how this worsening of symptoms is caused. The link leads us to interesting questions within the field of neurodegeneration. If you have a neurodegenerative disease, are you more prone to develop another? Are certain brains generally more susceptible to neurodegenerative disease or are they just unlucky random occurrences?
Substantia Nigra in Alzheimer’s disease: Burns, J., Galvin, J., Roe, C., Morris, J. and McKeel, D. (2005). The pathology of the substantia nigra in Alzheimer disease with extrapyramidal signs. Neurology, 64(8), pp.1397-1403.
α-synuclein in Alzheimer’s: Arai, Y., Yamazaki, M., Mori, O., Muramatsu, H., Asano, G. and Katayama, Y. (2001). α-Synuclein-positive structures in cases with sporadic Alzheimer’s disease: morphology and its relationship to tau aggregation. Brain Research, 888(2), pp.287-296.
Casey Morris PhD student, University of Southampton