Neuronal CD59 isoforms IRIS-1 and IRIS-2 as regulators of neurotransmitter release with implications for Alzheimer’s disease
(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.
(Less)
- author
- Golec, Ewelina
LU
; Olsson, Robin
LU
; Tuysuz, Emre Can LU ; Karlsson, Maja LU ; Serjieh, Yasmin LU ; King, Ben C. LU
; Wennström, Malin LU and Blom, Anna M. LU
- organization
- publishing date
- 2025
- 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
-
- pmid:39773760
- scopus:85214251368
- 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
- 2025-07-31 03:53:30
@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}}, }