Abstract Body

Expression levels of αsyn have been intimately linked to Lewy body disease pathogenesis with the transmission of αsyn pathology from cell-to-cell via synaptically-interconnected brain regions presumably contributing to the progression of disease. Downregulating alpha-synuclein expression has the potential to decrease pathology transmission, seeding, and aggregation, and significantly slow or even halt the progression of symptoms in patients with Lewy body diseases. Consistent with this hypothesis, regions that are typically spared in dementia with Lewy bodies, such as the visual cortex and cerebellum, have consistently lower levels of alpha-synuclein expression compared to regions that are more vulnerable to developing Lewy pathology.

Downregulation of alpha-synuclein is an attractive disease-modifying strategy because it holds the promise of delayed progression and neuroprotective benefits. In support of an alpha-synuclein downregulation strategy, multiple preclinical studies have demonstrated the effectiveness of antisense oligonucleotides targeting SNCA in reducing alpha-synuclein expression and mitigating related cellular dysfunction.

Here we will discuss alternative strategies to target alpha-synuclein expression levels including the use of small molecules and gene-editing technologies. Both offer an alternative strategy to modulate disease progression from those currently in clinical trials and will inform the efficacy of alpha-synuclein lowering strategies.