Harvey McMahon

Parkinson’s: generating a cell based model to understand disease
Group Leader page

Parkinson’s disease (PD) is second commonest neurodegenerative disease affecting 1% of the population, with age being the biggest risk factor. While the aetiology remains unknown, several genes have been discovered causing familial forms of PD. These genes implicate diverse cellular and neuronal processes with an emphasis on mitochondrial and/or lysosomal trafficking, resulting in the abnormal build up of protein aggregates and neuronal loss in the substantia nigra. Although familial forms account for less than 4% of PD, these phenomena are also found in sporadic cases of PD, providing a potent rationale to understand a molecular biology approach.

We have found that synuclein, a protein mutated in Parkinson’s maps to a pathway for mitochondrial quality control. We can show that the association and insertion of this protein into membranes is dependent on another protein mutated in Parkinson’s.

Aims

Our research over the past number of years has followed Parkinson’s in post-mortem brain through animal models to in vitro cell based assays. We would like to develop the cell based assays so that we can:

  1. study how the role of environmental factors in the disease
  2. study how disruption of membrane trafficking leads to aggregation of synuclein protein or potentially the reverse
  3. study how our newly identified pathway for synuclein activity relates to the activity of other mutated proteins in the disease.

Our hope is that this study will allow us to understand the mechanisms of PD from a cell biology perspective, but will also enable us to delve deeper into functional aspects of the disease. Our lab has acquired unique insights from our understanding of the biophysical mechanisms of alpha-synuclein/membrane interaction. This project will expand these finding and  develop a cell based assay aimed at screening for useful future therapeutics.

References:

Boucrot, E., et. al. (2015).
Endophilin marks and controls a clathrin-independent endocytic pathway.
Nature, 517(7535), 460–465.

Boucrot, E., et. al. (2012).
Membrane fission is promoted by insertion of amphipathic helices and is restricted by crescent BAR domains.
Cell, 149(1), 124–136.

Llobet, A., Gallop, J. L., Burden, J. J. E., Camdere, G., Chandra, P., Vallis, Y., et al. (2011).
Endophilin drives the fast mode of vesicle retrieval in a ribbon synapse.
The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 31(23), 8512–8519.

Gunawardana, N., Almeida-Souza, L., Howard, G., Colussi, A., Barker, R.A. and McMahon, H.T.
An alpha-synuclein-dependent pathway for mitochondrial quality control.
Manuscript in preparation.


All these papers can be found on our website: endocytosis.org