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

Golec, Ewelina LU ; Olsson, Robin LU orcid ; Tuysuz, Emre Can LU ; Karlsson, Maja LU ; Serjieh, Yasmin LU ; King, Ben C. LU orcid ; Wennström, Malin LU and Blom, Anna M. LU orcid (2025) In Alzheimer's Research and Therapy 17(1).
Abstract

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... (More)

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.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer’s disease, CD59, Intracellular complement, IRIS-1, IRIS-2, Neurotransmitters release, SNARE, Tau hyperphosphorylation, Type 2 diabetes
in
Alzheimer's Research and Therapy
volume
17
issue
1
article number
11
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85214251368
  • pmid:39773760
ISSN
1758-9193
DOI
10.1186/s13195-024-01660-z
language
English
LU publication?
yes
id
2d800283-d65d-43c6-aad9-ba0e47b9ef69
date added to LUP
2025-03-12 15:07:10
date last changed
2025-08-14 04:54:35
@article{2d800283-d65d-43c6-aad9-ba0e47b9ef69,
  abstract     = {{<p>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.</p>}},
  author       = {{Golec, Ewelina and Olsson, Robin and Tuysuz, Emre Can and Karlsson, Maja and Serjieh, Yasmin and King, Ben C. and Wennström, Malin and Blom, Anna M.}},
  issn         = {{1758-9193}},
  keywords     = {{Alzheimer’s disease; CD59; Intracellular complement; IRIS-1; IRIS-2; Neurotransmitters release; SNARE; Tau hyperphosphorylation; Type 2 diabetes}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Alzheimer's Research and Therapy}},
  title        = {{Neuronal CD59 isoforms IRIS-1 and IRIS-2 as regulators of neurotransmitter release with implications for Alzheimer’s disease}},
  url          = {{http://dx.doi.org/10.1186/s13195-024-01660-z}},
  doi          = {{10.1186/s13195-024-01660-z}},
  volume       = {{17}},
  year         = {{2025}},
}