Neuronal CD59 isoforms IRIS-1 and IRIS-2 as regulators of neurotransmitter release with implications for Alzheimer's disease.

We have previously demonstrated that the intracellular, non-GPI anchored CD59 isoforms IRIS-1 and IRIS-2 (Isoforms Rescuing Insulin Secretion 1 and 2) are necessary for insulin secretion from pancreatic β-cells. While investigating their expression across human tissues, we identified IRIS-1 and IRIS-2 mRNA in the human brain, though their protein expression and function remained unclear. This study shows the presence of both IRIS-1 and 2 proteins in the human brain, specifically in neurons and astrocytes. In the neuroblastoma cell line (SH-SY5Y), both isoforms are intracellular, and their expression increases upon differentiation into mature neurons. Silencing IRIS-1 and 2 in SH-SY5Y cells reduces the SNARE complex formation, essential for synaptic vesicle exocytosis, leading to a reduction in noradrenaline secretion. Notably, we observed diminished expression of neuronal IRIS-1 and 2 in patients with Alzheimer's disease (AD) and non-demented individuals with type 2 diabetes (T2D). In SH-SY5Y cells, knockdown of all isoforms of CD59 including IRIS-1 and 2 not only elevates phosphorylated tau but also increases cyclin-dependent kinase 5 (CDK5) expression, known promoter of hyperphosphorylation and accumulation of tau, a key pathological feature of AD. Additionally, we found that prolonged exposure to high glucose or cytokines markedly reduces the expression of IRIS-1 and 2 in SH-SY5Y cells, suggesting a link between AD pathology and metabolic stress through modulation of these isoforms. © 2024. The Author(s).

Citation

Ewelina Golec, Robin Olsson, Emre Can Tuysuz, Maja Karlsson, Yasmin Serjieh, Ben C King, Malin Wennström, Anna M Blom. Neuronal CD59 isoforms IRIS-1 and IRIS-2 as regulators of neurotransmitter release with implications for Alzheimer's disease. Alzheimer's research & therapy. 2025 Jan 07;17(1):11

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PMID: 39773760

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