Aβ exacerbates α-synuclein-induced neurotoxicity through impaired insulin signaling in α-synuclein-overexpressed human SK-N-MC neuronal cells.

Aim: α-Synuclein (αSyn) is known as a small soluble protein abundantly expressed in neuronal cells. Although its physiological role is still unclear, the aggregation of αSyn has been recognized as responsible for some neurodegenerative disorders such as dementia with Lewy bodies (DLB). In most cases, intracellular abnormal aggregates are caused by protein-coding mutations that alter primary structure and therefore increase propensity toward aggregation. However, no pathogenic alterations or polymorphisms in αSyn are found in DLB patients so far, suggesting genetic mutations may not play a major role in DLB pathogenesis. In contrast, emerging evidence reveals that amyloid β (Aβ) may contribute to aggregate formation and exacerbate neurotoxicity of αSyn. However, the underlying mechanism of action has remained unclear.

Methods: To investigate molecular pathways involved in Aβ-mediated αSyn pathology, we established an in vitro model for inducible αSyn overexpression in SK-N-MC human neuronal cells.

Results: Our results demonstrated that Aβ treatment in αSyn-overexpressed neuronal cells significantly increases αSyn intracellular aggregation and cytotoxicity. Moreover, Aβ also caused AMP-activated protein kinase (AMPK) inhibition and impaired insulin sensitivity, which leads to significant downregulation of nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1) antioxidant signaling to elicit αSyn aggregation.

Conclusions: This raised the possibility that insulin resistance could be one of the causative factors of αSyn toxicity, and the strategies for insulin sensitization may have therapeutic potential for synucleinopathies including DLB.