Q&A – David Rubinsztein

David Rubinsztein

Around one person in every 500 – some 120 000 people in the UK – develops Parkinson’s disease. Professor David Rubinsztein, a Wellcome Trust Senior Research Fellow at the Cambridge Institute for Medical Research, studies how genetic mutations lead to neurodegenerative diseases. A recent paper from his group revealed more about how certain mutations may cause toxicity in neurons in forms of Parkinson’s.

What is α-synuclein?
α-synuclein is a protein that is the predominant component of the clumps seen in neurons in Parkinson’s disease. Recent discoveries have shown that certain people have extra copies of the α-synuclein gene, and these people develop early-onset forms of Parkinson’s disease.

What was the aim of your study?
Our study looked at whether autophagy – a process through which cells engulf cytoplasm, organelles and protein complexes and deliver them for degradation – is abnormal when α-synuclein is overexpressed. This evolved from one of our earlier studies, which found that α-synuclein enhanced the aggregation of mutant forms of huntingtin [the protein associated with Huntington's disease]. We later discovered that mutant huntingtin was degraded by autophagy. The question was: does α-synuclein block autophagy?

What did you find?
Increased levels of α-synuclein do indeed block autophagy. This could explain some of the key pathologies you see in Parkinson’s disease. First, it’s plausible that since this extra α-synuclein does impede autophagy, then cells will be more prone to developing protein aggregates.

Second, one of the common abnormalities in Parkinson’s disease is malfunction of the mitochondria within cells. Unhealthy mitochondria produce increased levels of reactive oxygen species, among other things, which are harmful to a cell. Since autophagy can selectively remove and degrade malfunctioning mitochondria, these will be more likely to accumulate when there is excess α-synuclein.

How does Rab1a fit into this?
Rab1a was a clue that we got from a study by Susan Lindquist’s lab at the Whitehead Institute in the USA. It’s a molecule that helps to transport proteins when they are first produced (this is known as the early secretory pathway). Lindquist’s group found that Rab1a activity was impaired in a yeast model of Parkinson’s disease. They also found they could overcome some of the toxicity of α-synuclein in fruit-fly and cultured neuron models of Parkinson’s disease by overexpressing Rab1a. mWe tested whether decreased activity of Rab1a impaired autophagy. And indeed it did. Interestingly, we also found that if we overproduce Rab1a, it can counteract the impaired autophagy caused by high levels of α-synuclein.

What are the implications of your findings?
Our data provide some plausible explanations for the cellular abnormalities you see in Parkinson’s disease. Certainly, too much α-synuclein is not a good thing. But the effects we see are only a partial block on autophagy, not a full block. The question is: is that significant? Over many decades of life, as is the scenario in Parkinson’s disease, I think it is likely to be of consequence. But autophagy is probably just one of the players in the orchestra regulating cellular health in Parkinson’s disease.

Our data also tell us how disrupting some of the machinery involved in the early secretory pathway might have an impact on autophagy. However, some of our data suggest that disrupting other machinery involved in the early secretory pathway does not result in the same type of block in autophagy. So there may be some specificity to the way Rab1a works in this context.

What’s next for your research?
We need to understand how exactly α-synuclein is impairing Rab1a function. It is likely – on the basis of the Lindquist data – that if one impairs Rab1a function with α-synuclein you are also going to affect other aspects of cellular health. A molecular understanding of that will be challenging but useful. We also need to know how exactly Rab1a affects autophagy. That’s important not only from the disease perspective but also for understanding the relationship between signals coming from the early secretory pathway to autophagy, and the protein degradation in the rest of the cell. There are quite a few black boxes that need to be tackled there.

What do you do outside of work?
I’m a keen cellist and like listening to music. I also enjoy reading, particularly biographies.

Reference

Winslow AR et al. α-Synuclein impairs macroautophagy: implications for Parkinson’s disease. J Cell Biol 2010;190(6):1023-37.