What species of alpha-synuclein should be targeted for development of PD therapies?

Ever since human genetic studies revealed alpha-synuclein as a gene linked to the development of PD (Polymeropoulos et al, 1997), researchers have been trying to identify exactly what it is about alpha-synuclein that leads to the development of PD. In this inaugural article for alpha-synuclein based therapies, I am going to briefly discuss whether or not we have any progress in validating specific alpha-synuclein characteristics as key to the development of PD, and thereby warranting efforts towards drug discovery.

The first question to ask ourselves is: ‘Is alpha-synuclein a validated target?' Yes. Extra gene copies (Singleton et al, 2003; Ross et al, 2008), promoter mutations (Maraganore et al, 2006; Pals et al, 2004) and point mutations of the SNCA gene (Polymeropoulos et al, 1997; Kruger et al, 1998; Zarranz et al, 2004) all lead to PD, in a highly penetrant manner. This establishes alpha-synuclein as a very important player in the development of PD. Do we have insight to common mechanisms of disease pathogenesis for all of these SNCA alterations? As yet no, but not for lack of trying.

Are there any forms of synuclein that have been validated? The most validated information for synuclein is that if you have extra gene copies, you get PD. This establishes that absolute levels of synuclein are a contributing factor to PD. To target synuclein levels, there are numerous approaches:

1. Targeting nucleic acid: siRNA, antisense, shRNA, miRNA (Wang et al, 2008)
2. Targeting transcription: txn factors that regulate synuclein expression (Scherzer et al, 2008)
3. Targeting synuclein turnover. While these are the safest routes to identification of a therapeutic for synuclein owning to the complete validation of synuclein levels as a target, each approach has its own technical challenges.

Given that increased levels of synuclein lead to PD, there may be a correlation between levels of synuclein and aggregation potential of synuclein. However, it is not clear at all how, or if, synuclein aggregation is protective or detrimental. Lewy bodies are the pathological hallmark of PD, and are composed of highly aggregated, oftentimes fibrillar synuclein. However, because the surviving DA neurons contain Lewy bodies, one can make the argument that the cells that were able to fully aggregate synuclein were somehow protected. Cells that are not able to fully aggregate synuclein may be exposed to more detrimental cytoplasmic events. This may mean that there is a form of synuclein aggregate that is an off-pathway aggregate and will never result in a fibrillar lewy body, and creates a toxic stress for the cell.

Another outcome of too much synuclein may be that excess amounts of monomer synuclein are altering an otherwise normal cellular function. For example, if alpha-syn is responsible for helping to regulate neurotransmitter release at the synapse (Yavich et al, 2004), alterations in alpha-syn levels may alter the rate, or efficiency of that process in a negative way.

Increased levels of synuclein may also lead to excessive amounts of a modified form of synuclein. For example, excess monomer synuclein may be fine for a cell, but eventually leads to more phosphorylated (Inglis et al, 2009), nitrated (Paxinou et al, 2001), truncated (Baba et al, 1998), and/or dopamine-adducted synuclein (Conway et al, 2001). All of these modified forms of synuclein have been identified in PD tissue. As yet, none of these forms of synuclein have been validated to cause disease despite large efforts, suggesting this validation step is not trivial.

A useful tool to validate synuclein hypotheses is the use of the point mutations linked to synuclein. Does A30P, A53T or E46K lead to greater phospho-syn? Are the aggregation kinetics of fibril formation altered for any of these mutants? Do they create a more, or less, stable form of synuclein, i.e, do they increase levels of alpha-syn? In vitro studies can demonstrate specific kinetic pathways of aggregation-with determinations of likelihood of forming fibrils or off-pathway aggregates using different mutations. In vitro studies have been informative but the big challenge in the field is to correlate that with cellular studies. So far, there is no clear effect on synuclein that occurs with all identified mutations and correlates to similar effect in cells.

It may be that specific point mutations change the ability of a-synuclein binding proteins to interact. Synphilin-1 (Engelender et al, 1999) and alpha-p25 (Lindersson et al, 2005) have been shown to increase aggregation potential of alpha-syn, and sept4 has been shown to decrease aggregation of alpha-syn (Ihara et al, 2007). Perhaps these binding sites on synuclein are a starting point to target as an anti-aggregation compound for monomer synuclein?

Alpha-synuclein is by far the most validated target for Parkinson's Disease. It has also proven to be the most difficult target to reveal the nature of it's role in pathogenesis of PD.

Hello,

I have heard about the following study, which form of alpha-synuclein was used and is there any more information on the outcomes of this study?

" Elan and collaborators at the University of California, San Diego, USA, have reported promising of a vaccine approach to treating Parkinson's and other Lewy Body diseases, in mice.

Rodents were injected with the abnormal form of alpha-synuclein that aggregates in the brains of LB patients and..".