Parkinson’s Disease (PD):My research focuses on elucidating the cell and molecular mechanisms underlying Parkinson’s disease. Over the past  20 years my research has focussed on the role of mitochondrial dysfunction in PD brains (Schapira et al 1990)  and platelets (Krige et al 1994) and its relationship to other features detected in PD brains including ; mitochondrial DNA defects (Gu et al 1998 ),  nitric oxide (Cleeter et al 1994), oxidative stress (Seaton et al 1997), iron (Hartley et al 1993) and cell death (Hartley et al 1994).  Increasingly with the identification of the familial causes of PD my research has turned to the role of specific mutant genes in PD pathogenesis. Alpha-synuclein has been my main focus with additional interests in ; LRRK2 (Papkovskaia et al 2012), parkin (Gegg et al 2010) and glucocerebrosidase (Gegg et al 2012). While mitochondrial biochemistry is a recurrent theme I also have a broader interest including dopamine metabolism (Tabrizi et al 2000), protein degradation pathways (Alvarez-Erviti et al 2010), alpha-synuclein aggregation and transmission (Alvarez-Erviti et al 2011) and microRNA dysregulation (Alvarez-Erviti et al 2013).

Alpha-synuclein : alpha-synuclein pathology is at the core of PD. I am interested in the normal function of alpha-synuclein. I have a project investigating the regulation of S129 phosphorylation, (Chau et al 2009) and how it may affect its function.I am interested in the cellular handling of alpha-synuclein in particular the pathways of its degradation and how these may be affected in PD. We have identified a deficiency of hsc70 and LAMP2A proteins in PD brains (Alvarez-Erviti et al 2010) which may be responsible for the cellular increase in alpha-synuclein levels in PD.   In addition we are studying what factors influence its; oligomerisation, aggregation and  transmission of synuclein aggregates between cells and the role of exosomes in this process (Alvarez-Erviti et al 2011) . In collaboration with Lydia Alvarez I have a project investigating the role of microRNA dysregulation in PD and how this relates to other pathological findings. We have identified specific microRNAs that can regulate hsc70 and LAMP2A expression which are dramatically elevated in PD brains possibly explaining the observed changes (Alvarez-Erviti et al 2013). We are now investigating the mechanisms underpinning the microRNA dysregulation. I have a collaboration with Lydia Alvarez studying the potential of RVG modified exosome as an in vivo vehicle for the delivery of siRNAs to murine CNS to down-regulate alpha-synuclein.  This is using various cell lines and the human S129D alpha-synuclein transgenic mouse model which shows alpha-synuclein aggregation. This is an exciting new system which has the potential to treat PD by preventing the increased alpha-synuclein aggregation and its transmission between neurons with disease progression.