Targeting Alpha-Synuclein

Alpha-synuclein (Park1/SNCA) has been identified as a genetic risk factor for PD, and the presence of aggregates of alpha-synuclein in the brain is a defining histopathological feature of PD.

Thus the regulation of alpha-synuclein handling processes, including those associated with protein trafficking and aggregation, present promising targets for therapeutic development. Some therapeutic approaches attempt to either prevent development of or dissolve existing protein aggregates. Numerous compounds have been tested as inhibitors of alpha-synuclein aggregation (Abe et al., 2007). Some catechols, flavonoids and related compounds have the potential to inhibit fibrillation of alpha-synuclein and disaggregate existing fibrils. Statins were recently shown to reduce neuronal alpha-synuclein aggregation in cell line models of PD (Bar-On et al., 2008).

Aggregation is also thought to be caused by increased alpha-synuclein expression. Direct infusion of chemically modified (naked), murine-specific siRNA into the hippocampus has been shown to significantly reduce SNCA levels. Reduction of SNCA in the hippocampus and cortex persisted for a minimum of one week post-infusion with recovery nearing control levels by 3 weeks post-infusion. This technique may lead to a possible therapeutic treatment to decrease levels of alpha-synuclein in the PD brain. Evidence demonstrates that alpha-synculein (but not beta-synuclein) is degraded via chaperone-mediated autophagy and macroautophagy, possibly providing other avenues to address alpha-synuclein clearance (Kabuta et al., 2008).

Molecular chaperones have been targeted to improve handling of alpha-synuclein within the cell, as well as normal trafficking pathways. These include Hsp70-mediated inhibition of fibril assembly (Luk et al., 2008) and alpha-synuclein interference of Rab trafficking functions (Gitler et al., 2008).