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Ferreira CB, Marttinen M, Coelho JE, et al. S327 phosphorylation of the presynaptic protein SEPTIN5 increases in the early stages of neurofibrillary pathology and alters the functionality of SEPTIN5. Neurobiol Dis. 2021;163:105603doi: 10.1016/j.nbd.2021.105603.
Ferreira, C. B., Marttinen, M., Coelho, J. E., Paldanius, K. M. A., Takalo, M., Mäkinen, P., Leppänen, L., Miranda-Lourenço, C., Fonseca-Gomes, J., Tanqueiro, S. R., Vaz, S. H., Belo, R. F., Sebastião, A. M., Leinonen, V., Soininen, H., Pike, I., Haapasalo, A., Lopes, L. V., de Mendonça, A., Diógenes, M. J., & Hiltunen, M. (2021). S327 phosphorylation of the presynaptic protein SEPTIN5 increases in the early stages of neurofibrillary pathology and alters the functionality of SEPTIN5. Neurobiology of disease, 163105603. https://doi.org/10.1016/j.nbd.2021.105603
Ferreira, Catarina B, et al. "S327 phosphorylation of the presynaptic protein SEPTIN5 increases in the early stages of neurofibrillary pathology and alters the functionality of SEPTIN5." Neurobiology of disease vol. 163 (2021): 105603. doi: https://doi.org/10.1016/j.nbd.2021.105603
Ferreira CB, Marttinen M, Coelho JE, Paldanius KMA, Takalo M, Mäkinen P, Leppänen L, Miranda-Lourenço C, Fonseca-Gomes J, Tanqueiro SR, Vaz SH, Belo RF, Sebastião AM, Leinonen V, Soininen H, Pike I, Haapasalo A, Lopes LV, de Mendonça A, Diógenes MJ, Hiltunen M. S327 phosphorylation of the presynaptic protein SEPTIN5 increases in the early stages of neurofibrillary pathology and alters the functionality of SEPTIN5. Neurobiol Dis. 2021 Dec 24;163:105603. doi: 10.1016/j.nbd.2021.105603. Epub 2021 Dec 24. PMID: 34954322.
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Neurobiol Dis. 2021 Dec 24;163:105603. doi: 10.1016/j.nbd.2021.105603. Epub 2021 Dec 24.

S327 phosphorylation of the presynaptic protein SEPTIN5 increases in the early stages of neurofibrillary pathology and alters the functionality of SEPTIN5.

Neurobiology of disease

Catarina B Ferreira, Mikael Marttinen, Joana E Coelho, Kaisa M A Paldanius, Mari Takalo, Petra Mäkinen, Luukas Leppänen, Catarina Miranda-Lourenço, João Fonseca-Gomes, Sara R Tanqueiro, Sandra H Vaz, Rita F Belo, Ana Maria Sebastião, Ville Leinonen, Hilkka Soininen, Ian Pike, Annakaisa Haapasalo, Luísa V Lopes, Alexandre de Mendonça, Maria José Diógenes, Mikko Hiltunen

Affiliations

  1. Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
  2. Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; Structural and Computational Biology, European Molecular Biology Laboratory, Heidelberg, Germany.
  3. Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
  4. Institute of Clinical Medicine - Neurosurgery, University of Eastern Finland, Kuopio, Finland; Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland.
  5. Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
  6. Proteome Sciences plc, London, United Kingdom.
  7. A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
  8. Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
  9. Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal. Electronic address: [email protected].
  10. Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland. Electronic address: [email protected].

PMID: 34954322 DOI: 10.1016/j.nbd.2021.105603

Abstract

Alzheimer's disease (AD) is the most common form of dementia, which is neuropathologically characterized by extracellular senile plaques containing amyloid-β and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Previous studies have suggested a role for septin (SEPTIN) protein family members in AD-associated cellular processes. Here, we elucidated the potential role of presynaptic SEPTIN5 protein and its post-translational modifications in the molecular pathogenesis of AD. RNA and protein levels of SEPTIN5 showed a significant decrease in human temporal cortex in relation to the increasing degree of AD-related neurofibrillary pathology. Conversely, an increase in the phosphorylation of the functionally relevant SEPTIN5 phosphorylation site S327 was observed already in the early phases of AD-related neurofibrillary pathology, but not in the cerebrospinal fluid of individuals fulfilling the criteria for mild cognitive impairment due to AD. According to the mechanistic assessments, a link between SEPTIN5 S327 phosphorylation status and the effects of SEPTIN5 on amyloid precursor protein processing and markers of autophagy was discovered in mouse primary cortical neurons transduced with lentiviral constructs encoding wild type SEPTIN5 or SEPTIN5 phosphomutants (S327A and S327D). C57BL/6 J mice intrahippocampally injected with lentiviral wild type SEPTIN5 or phosphomutant constructs did not show changes in cognitive performance after five to six weeks from the start of injections. However, SEPTIN5 S327 phosphorylation status was linked to changes in short-term synaptic plasticity ex vivo at the CA3-CA1 synapse. Collectively, these data suggest that SEPTIN5 and its S327 phosphorylation status play a pivotal role in several cellular processes relevant for AD.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: APP processing; Alzheimer's disease; Autophagy; Aβ; Post-translational modifications; SEPTIN5; Synaptic plasticity

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