Harvey McMahon

Molecular mechanism of Parkinson’s disease
Group Leader page

Project 1: Parkinson’s disease: the importance of mitochondria to maintenance of synaptic function

Synaptic dysfunction has long been known to play a role in the onset of Parkinson’s. Drugs that affect neuronal synaptic function can induce Parkinsonian symptoms while mutations of the mitochondrial PINK and PARKIN proteins are found in patients with the disease.

This project aims to find out what happens to synapses when mitochondrial stop functioning optimally. We have found in fibroblast models, that a number of risk factor proteins for Parkinson’s affect mitochondrial function. We would now like to move this work from fibroblasts into neurons where mitochondria are enriched in synapses and are necessary for synaptic function. Here we will study endocytosis and exocytosis in cultured neurons while manipulation risk factors for the disease.

Understanding how mitochondria contribute to synaptic function and equally how dysfunction contributes to neuronal loss may be key to understanding the progression the disease. In addition, we hope this work will contribute useful mechanisms to be able to protect against energy deficits and thus increase neuronal health to protect against disease progression.

We will try to understand the normal function of risk factors for the disease. In addition we will be looking for new drug targets to protect against mitochondrial dysfunction.

References:

Simcox, E. M., Reeve, A., & Turnbull, D. (2013).
Monitoring mitochondrial dynamics and complex I dysfunction in neurons: implications for Parkinson's disease.
Biochemical Society Transactions, 41(6), 1618–1624.

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.

Peter, B. J., et. al. (2004).
BAR domains as sensors of membrane curvature: the amphiphysin BAR structure.
Science (New York, N.Y.), 303(5657), 495–499.


Project 2:  Parkinsons: what goes wrong at a molecular level

Parkinson’s disease (PD) is second commonest neurodegenerative disease affecting 1% of the population, with age being the biggest risk factor. Patients usually present with pronounced motor features. 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. The neuronal loss and abnormal protein aggregates are also found in sporadic cases of PD providing a potent rationale to further investigate the genes in familial PD with an understanding that common pathways may be found.

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 resulting in vesicle formation.

Aims

Our aim is to study potential interactions between these proteins with a view to positioning the disease proteins in cell biology pathways leading to an understanding of the molecular mechanisms of PD. Using well-established assays in our lab we will:

  1. aim to assess binary interactions between PD-related proteins.
  2. search for novel interactors of PD-related proteins, identifying potentially new molecular mechanisms in PD
  3. study how and where all these proteins function in a cell
  4. 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 structural and functional aspects of the disease. Our lab has a unique angle on this disease coming from our understanding of how proteins like alpha-synuclein works from a biophysical level, and this knowledge has led us to the insights we have already. This project will build on this knowledge and will hopefully inform 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.

Peter, B. J., et. al. (2004).
BAR domains as sensors of membrane curvature: the amphiphysin BAR structure.
Science (New York, N.Y.), 303(5657), 495–499.


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