Reducing the expression of alpha-synuclein

Human genetic studies suggest that a-syn overexpression correlates with PD, at least in the PD cases that have multiplications of the a-syn gene. Targeting a-syn expression itself may be an effective neuroprotective therapy for an a-synucleinopathy. Recent developments highlight the current focus onRNA interference (RNAi)-mediated knockdown of asyn mRNA, thus offering protection for dopaminergic neuroblastoma cells as well as in in vivo model systems. RNAi approaches continue to make strides toward broad use in the clinic, and delivery to the central nervous system will represent one of the most difficult challenges.
If a-syn expression is required for pathogenesis, targeting a-syn mRNA should provide neuroprotection or neurorestoration or both. Outside of RNAi approaches, the asyn promoter may represent a viable target to knockdown asyn expression. GATA-2 critically induces a-syn expression, and inhibitory agents blocking transcription activation may enable therapeutically beneficial lower production of asyn,
at least in those PD patients with a-syn gene multiplications. Transcriptional regulation of a-syn through NGF- and bFGF-mediated signal transduction via the MAP-ERK and PI3 kinase pathways may also serve to regulate a-syn expression
and provide neuroprotection. Both the proteasome and lysosomal degradation pathways
seem important for clearance of a-syn and a-syn–containing protein aggregates. Enhancing proteosomal function by overexpressing parkin (E3 ubiquitin ligase) reduces a-syn toxicity in model systems, including preservation of TH positive
neurons in the substantia nigra and sparing of TH positive nerve terminals in the striatum. Decreasing a-syn ubiquitination by blocking the E3 ubiquitin-ligase SIAH
reduces the amounts of amorphous aggregates formed in cells. The action of PD-associated point mutations may impair normal metabolism through chaperone-mediated autophagy. Afterward, upregulation of cathepsin D to enhance lysosomal function promotes a-syn degradation and inhibits aggregation and toxicity. A small proportion of a-syn also exists outside of the cell and in the cerebrospinal
fluid. a-Syn vaccination may be another strategy to reduce a-syn protein levels with proof of concept demonstrated in a transgenic model in which immunization reduced
aggregation and neurotoxicity.