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The role of septins on synaptic function and on amyloid precursor protein processing
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S327 phosphorylation of the presynaptic protein SEPTIN5 increases in the early stages of neurofibrillary pathology and alters the functionality of SEPTIN5
Publication . Ferreira, Catarina B.; Marttinen, Mikael; Coelho, Joana E; Paldanius, Kaisa M.A.; Takalo, Mari; Mäkinen, Petra; Leppänen, Luukas; Miranda-Lourenço, Catarina; Fonseca-Gomes, João; Tanqueiro, Sara; Vaz, Sandra H.; Belo, Rita F.; Sebastião, Ana M; Leinonen, Ville; Soininen, Hilkka; Pike, Ian; Haapasalo, Annakaisa; Lopes, Luisa V.; De Mendonça, Alexandre; Diógenes, Maria José; Hiltunen, Mikko
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.
The role of septins on synaptic function and on amyloid precursor protein processing
Publication . Ferreira, Catarina B.; Diógenes, Maria José; Mendonça, Alexandre de; Hiltunen, Mikko
Alzheimer’s disease (AD) is a most devasting form of neurodegenerative disorders, pathologically characterized by neuronal cell degeneration and death, extracellular senile plaques containing amyloid beta (Aβ) and intra-cellular neurofibrillary tangles composed by hyperphosphorylated tau pro-tein. At the molecular and cellular level, AD is associated with a drastic increase of soluble Aβ peptide levels at specific regions in the brain, along-side with deficits in synaptic plasticity, and brain-derived neurotrophic fac-tor (BDNF) signaling impairment. Previous studies have suggested a role for septin (SEPT) protein family members in the cellular processes relevant for AD. The present work thus aimed to elucidate the potential role of pre-synaptic SEPT5 protein and its post-translational modifications in the mo-lecular pathogenesis of AD.
Both messenger ribonucleic acid and protein levels of SEPT5 were signifi-cantly decreased in the late stages of AD-related neurofibrillary pathology in well-characterized human post-mortem temporal cortical tissue samples. On the contrary, a significant increase in the phosphorylation of the func-tionally relevant SEPT5 phosphorylation site serine 327 residue (S327) was observed already in the early stages of AD-related neurofibrillary pathol-ogy, but not in the cerebrospinal fluid of patients with mild cognitive im-pairment due to AD. A dependency between SEPT5 S327 phosphorylation status and the effects of SEPT5 on amyloid precursor protein processing and Aβ generation was not observed in the mouse primary cortical neurons transduced with SEPT5 wild type (SEPT5-wt) and its S327 mutants (serine to alanine (S327A) and serine to aspartate (S327D)) lentiviral constructs. Moreover, C57BL/6J mice intrahippocampally injected with lentiviral SEPT5 constructs did not show any cognitive or behavioral deficits, after five to six weeks of overexpression of SEPT5 and its S327 mutants. How-ever, SEPT5 S327 phosphorylation status was linked to changes in short-term plasticity ex vivo at the cornu ammonis (CA) 3-CA1 synapse. Finally, the levels both of the precursor form of BDNF (pro-BDNF) and BDNF in cell culture lysates as well as BDNF levels in cell culture lysates and super-natants were not different in the SEPT5-overexpressing cells. Furthermore, the intracellular domain of tropomyosin-receptor kinase B did not induce SEPT5 phosphorylation at S327.
In conclusion, the work presented here underscores the role of SEPT5 and its S327 phosphorylation status, providing important insights into several cellular processes relevant for the pathogenesis of AD.
Challenges of BDNF-based therapies : from common to rare diseases
Publication . Miranda-Lourenço, Catarina; Ribeiro Rodrigues, Leonor; Fonseca-Gomes, João; Tanqueiro, Sara; Belo, Rita F.; Ferreira, Catarina B.; Rei, Nádia; Ferreira-Manso, Mafalda; de Almeida-Borlido, Carolina; Costa-Coelho, Tiago; Freitas, Céline; Zavalko, Svitlana; Mouro, Francisco; Sebastião, Ana M; Xapelli, Sara; Rodrigues, Tiago M.; Diógenes, Maria José
Neurotrophins are a well-known family of neurotrophic factors that play an important role both in the central and peripheral nervous systems, where they modulate neuronal survival, development, function and plasticity. Brain-derived neurotrophic factor (BDNF) possesses diverse biological functions which are mediated by the activation of two main classes of receptors, the tropomyosin-related kinase (Trk) B and the p75 neurotrophin receptor (p75NTR). The therapeutic potential of BDNF has drawn attention since dysregulation of its signalling cascades has been suggested to underlie the pathogenesis of both common and rare diseases. Multiple strategies targeting this neurotrophin have been tested; most have found obstacles that ultimately hampered their effectiveness. This review focuses on the involvement of BDNF and its receptors in the pathophysiology of Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Rett Syndrome (RTT). We describe the known mechanisms leading to the impairment of BDNF/TrkB signalling in these disorders. Such mechanistic insight highlights how BDNF signalling compromise can take various shapes, nearly disease-specific. Therefore, BDNF-based therapeutic strategies must be specifically tailored and are more likely to succeed if a combination of resources is employed.
Presynaptic vesicle protein SEPTIN5 regulates the degradation of APP C-Terminal fragments and the levels of Aβ
Publication . Marttinen, Mikael; Ferreira, Catarina B.; Paldanius, Kaisa M. A.; Takalo, Mari; Natunen, Teemu; Mäkinen, Petra; Leppänen, Luukas; Leinonen, Ville; Tanigaki, Kenji; Kang, Gina; Hiroi, Noboru; Soininen, Hilkka; Rilla, Kirsi; Haapasalo, Annakaisa; Hiltunen, Mikko
Alzheimer's disease (AD) is a neurodegenerative disease characterized by aberrant amyloid-β (Aβ) and hyperphosphorylated tau aggregation. We have previously investigated the involvement of SEPTIN family members in AD-related cellular processes and discovered a role for SEPTIN8 in the sorting and accumulation of β-secretase. Here, we elucidated the potential role of SEPTIN5, an interaction partner of SEPTIN8, in the cellular processes relevant for AD, including amyloid precursor protein (APP) processing and the generation of Aβ. The in vitro and in vivo studies both revealed that the downregulation of SEPTIN5 reduced the levels of APP C-terminal fragments (APP CTFs) and Aβ in neuronal cells and in the cortex of Septin5 knockout mice. Mechanistic elucidation revealed that the downregulation of SEPTIN5 increased the degradation of APP CTFs, without affecting the secretory pathway-related trafficking or the endocytosis of APP. Furthermore, we found that the APP CTFs were degraded, to a large extent, via the autophagosomal pathway and that the downregulation of SEPTIN5 enhanced autophagosomal activity in neuronal cells as indicated by altered levels of key autophagosomal markers. Collectively, our data suggest that the downregulation of SEPTIN5 increases the autophagy-mediated degradation of APP CTFs, leading to reduced levels of Aβ in neuronal cells.
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
OE
Número da atribuição
PD/BD/128390/2017