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Article: Molecular mechanisms of necroptosis and relevance for neurodegenerative diseases.

Dionísio, Pedro A / Amaral, Joana D / Rodrigues, Cecília M P

International review of cell and molecular biology

2020 Volume 353, Page(s) 31–82

Abstract: Necroptosis is a regulated cell death pathway morphologically similar to necrosis that depends on the kinase activity of receptor interacting protein 3 (RIP3) and the subsequent activation of the pseudokinase mixed lineage kinase domain-like protein ( ... ...

Abstract	Necroptosis is a regulated cell death pathway morphologically similar to necrosis that depends on the kinase activity of receptor interacting protein 3 (RIP3) and the subsequent activation of the pseudokinase mixed lineage kinase domain-like protein (MLKL), being also generally dependent on RIP1 kinase activity. Necroptosis can be recruited during pathological conditions, usually following the activation of death receptors under specific cellular contexts. In this regard, necroptosis has been implicated in the pathogenesis of multiple disorders, including acute and chronic neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases, and multiple sclerosis. Here, we summarize the molecular mechanisms regulating the induction of necroptosis and downstream effectors of this form of cell death, besides exploring non-necroptotic roles for necroptosis-related proteins that may impact on alternative cell death pathways and inflammatory mechanisms in disease. Finally, we outline the recent evidence implicating necroptosis in neurodegenerative conditions and the emerging therapeutic perspectives targeting necroptosis in these diseases.
MeSH term(s)	Animals ; Humans ; Necroptosis ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology
Language	English
Publishing date	2020-02-13
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2427220-6
ISSN	1937-6448 ; 0074-7696
ISSN	1937-6448 ; 0074-7696
DOI	10.1016/bs.ircmb.2019.12.006
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Article ; Online: Lack of peroxisomal catalase affects heat shock response in

Musa, Marina / Dionisio, Pedro A / Casqueiro, Ricardo / Milosevic, Ira / Raimundo, Nuno / Krisko, Anita

Life science alliance

2022 Volume 6, Issue 1

Abstract: Exact mechanisms of heat shock-induced lifespan extension, although documented across species, are still not well understood. Here, we show that fully functional peroxisomes, specifically peroxisomal catalase, are needed for the activation of canonical ... ...

Abstract	Exact mechanisms of heat shock-induced lifespan extension, although documented across species, are still not well understood. Here, we show that fully functional peroxisomes, specifically peroxisomal catalase, are needed for the activation of canonical heat shock response and heat-induced hormesis in
MeSH term(s)	Animals ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/genetics ; Caenorhabditis elegans Proteins/metabolism ; Catalase/genetics ; Catalase/metabolism ; Heat-Shock Response ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Caenorhabditis elegans Proteins ; Catalase (EC 1.11.1.6) ; Transcription Factors
Language	English
Publishing date	2022-11-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202201737
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Article: miR-335 Targets LRRK2 and Mitigates Inflammation in Parkinson's Disease.

Oliveira, Sara R / Dionísio, Pedro A / Gaspar, Maria M / Correia Guedes, Leonor / Coelho, Miguel / Rosa, Mário M / Ferreira, Joaquim J / Amaral, Joana D / Rodrigues, Cecília M P

Frontiers in cell and developmental biology

2021 Volume 9, Page(s) 661461

Abstract: Parkinson's disease (PD) is mainly driven by dopaminergic neuronal degeneration in ... ...

Abstract	Parkinson's disease (PD) is mainly driven by dopaminergic neuronal degeneration in the
Language	English
Publishing date	2021-06-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2021.661461
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Article ; Online: Discovery of a Necroptosis Inhibitor Improving Dopaminergic Neuronal Loss after MPTP Exposure in Mice.

Oliveira, Sara R / Dionísio, Pedro A / Gaspar, Maria M / Ferreira, Maria B T / Rodrigues, Catarina A B / Pereira, Rita G / Estevão, Mónica S / Perry, Maria J / Moreira, Rui / Afonso, Carlos A M / Amaral, Joana D / Rodrigues, Cecília M P

International journal of molecular sciences

2021 Volume 22, Issue 10

Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disorder, mainly characterized by motor deficits correlated with progressive dopaminergic neuronal loss in the substantia nigra pars compacta (SN). Necroptosis is a caspase-independent ... ...

Abstract	Parkinson's disease (PD) is the second most common neurodegenerative disorder, mainly characterized by motor deficits correlated with progressive dopaminergic neuronal loss in the substantia nigra pars compacta (SN). Necroptosis is a caspase-independent form of regulated cell death mediated by the concerted action of receptor-interacting protein 3 (RIP3) and the pseudokinase mixed lineage domain-like protein (MLKL). It is also usually dependent on RIP1 kinase activity, influenced by further cellular clues. Importantly, necroptosis appears to be strongly linked to several neurodegenerative diseases, including PD. Here, we aimed at identifying novel chemical inhibitors of necroptosis in a PD-mimicking model, by conducting a two-step screening. Firstly, we phenotypically screened a library of 31 small molecules using a cellular model of necroptosis and, thereafter, the hit compound effect was validated in vivo in a sub-acute 1-methyl-1-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) PD-related mouse model. From the initial compounds, we identified one hit-Oxa12-that strongly inhibited necroptosis induced by the pan-caspase inhibitor zVAD-fmk in the BV2 murine microglia cell line. More importantly, mice exposed to MPTP and further treated with Oxa12 showed protection against MPTP-induced dopaminergic neuronal loss in the SN and striatum. In conclusion, we identified Oxa12 as a hit compound that represents a new chemotype to tackle necroptosis. Oxa12 displays in vivo effects, making this compound a drug candidate for further optimization to attenuate PD pathogenesis.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Brain/metabolism ; Cell Death/drug effects ; Corpus Striatum/metabolism ; Disease Models, Animal ; Dopamine/metabolism ; Dopaminergic Neurons/drug effects ; Dopaminergic Neurons/metabolism ; GTPase-Activating Proteins/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Microglia/metabolism ; Necroptosis/drug effects ; Necroptosis/physiology ; Neurodegenerative Diseases/metabolism ; Parkinson Disease/metabolism ; Pars Compacta/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Substantia Nigra/metabolism
Chemical Substances	GTPase-Activating Proteins ; Ralbp1 protein, mouse ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Ripk3 protein, mouse (EC 2.7.11.1) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2021-05-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22105289
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Article ; Online: Ablation of RIP3 protects from dopaminergic neurodegeneration in experimental Parkinson's disease.

Dionísio, Pedro A / Oliveira, Sara R / Gaspar, Maria M / Gama, Maria J / Castro-Caldas, Margarida / Amaral, Joana D / Rodrigues, Cecilia M P

Cell death & disease

2019 Volume 10, Issue 11, Page(s) 840

Abstract: Parkinson's disease (PD) is driven by dopaminergic neurodegeneration in the substantia nigra pars compacta (SN) and striatum. Although apoptosis is considered the main neurodegenerative mechanism, other cell death pathways may be involved. In this regard, ...

Abstract	Parkinson's disease (PD) is driven by dopaminergic neurodegeneration in the substantia nigra pars compacta (SN) and striatum. Although apoptosis is considered the main neurodegenerative mechanism, other cell death pathways may be involved. In this regard, necroptosis is a regulated form of cell death dependent on receptor interacting protein 3 (RIP3), a protein also implicated in apoptosis and inflammation independently of its pro-necroptotic activity. Here, we explored the role of RIP3 genetic deletion in in vivo and in vitro PD models. Firstly, wild-type (Wt) and RIP3 knockout (RIP3ko) mice were injected intraperitoneally with MPTP (40 mg/kg, i.p.), and sacrificed after either 6 or 30 days. RIP3ko protected from dopaminergic neurodegeneration in the SN of MPTP-injected mice, but this effect was independent of necroptosis. In keeping with this, necrostatin-1s (10 mg/kg/day, i.p.) did not afford full neuroprotection. Moreover, MPTP led to DNA fragmentation, caspase-3 activation, lipid peroxidation and BAX expression in Wt mice, in the absence of caspase-8 cleavage, suggesting intrinsic apoptosis. This was mimicked in primary cortical neuronal cultures exposed to the active MPTP metabolite. RIP3 deficiency in cultured cells and in mouse brain abrogated all phenotypes. Curiously, astrogliosis was increased in the striatum of MPTP-injected Wt mice and further exacerbated in RIP3ko mice. This was accompanied by absence of microgliosis and reposition of glial cell line-derived neurotrophic factor (GDNF) levels in the striata of MPTP-injected RIP3ko mice when compared to MPTP-injected Wt mice, which in turn showed a massive GDNF decrease. RIP3ko primary mixed glial cultures also presented decreased expression of inflammation-related genes upon inflammatory stimulation. These findings hint at possible undescribed non-necroptotic roles for RIP3 in inflammation and MPTP-driven cell death, which can contribute to PD progression.
MeSH term(s)	Animals ; Apoptosis/genetics ; Caspase 3/genetics ; Corpus Striatum/metabolism ; Corpus Striatum/pathology ; Dopaminergic Neurons/metabolism ; Dopaminergic Neurons/pathology ; Gene Expression Regulation/genetics ; Glial Cell Line-Derived Neurotrophic Factor/genetics ; Humans ; Mice, Knockout ; Necroptosis/genetics ; Nerve Degeneration/genetics ; Nerve Degeneration/pathology ; Neuroglia/metabolism ; Neuroglia/pathology ; Parkinson Disease/genetics ; Parkinson Disease/pathology ; Pars Compacta/metabolism ; Pars Compacta/pathology ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; bcl-2-Associated X Protein/genetics
Chemical Substances	Bax protein, mouse ; Glial Cell Line-Derived Neurotrophic Factor ; bcl-2-Associated X Protein ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Ripk3 protein, mouse (EC 2.7.11.1) ; Casp3 protein, mouse (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-)
Language	English
Publishing date	2019-11-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-019-2078-z
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Article ; Online: Circulating Inflammatory miRNAs Associated with Parkinson's Disease Pathophysiology.

Oliveira, Sara R / Dionísio, Pedro A / Correia Guedes, Leonor / Gonçalves, Nilza / Coelho, Miguel / Rosa, Mário M / Amaral, Joana D / Ferreira, Joaquim J / Rodrigues, Cecília M P

Biomolecules

2020 Volume 10, Issue 6

Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, being largely characterized by motor features. MicroRNAs (miRNAs) are small non-coding RNAs, whose deregulation has been associated with neurodegeneration in PD. In ... ...

Abstract	Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, being largely characterized by motor features. MicroRNAs (miRNAs) are small non-coding RNAs, whose deregulation has been associated with neurodegeneration in PD. In this study, miRNAs targeting cell death and/or inflammation pathways were selected and their expression compared in the serum of PD patients and healthy controls. We used two independent cohorts (discovery and validation) of 20 idiopathic PD patients (iPD) and 20 healthy controls each. We also analyzed an additional group of 45 patients with a mutation in the leucine-rich repeat kinase 2 (
MeSH term(s)	Aged ; Case-Control Studies ; Cohort Studies ; Female ; Humans ; Inflammation/blood ; Inflammation/genetics ; Inflammation/metabolism ; Male ; MicroRNAs/blood ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Parkinson Disease/blood ; Parkinson Disease/genetics ; Parkinson Disease/physiopathology
Chemical Substances	MicroRNAs
Language	English
Publishing date	2020-06-23
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom10060945
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Article ; Online: Amyloid β peptides promote autophagy-dependent differentiation of mouse neural stem cells: Aβ-mediated neural differentiation.

Fonseca, Maria B / Solá, Susana / Xavier, Joana M / Dionísio, Pedro A / Rodrigues, Cecília M P

Molecular neurobiology

2013 Volume 48, Issue 3, Page(s) 829–840

Abstract: Although regarded as neurotoxic, amyloid β (Aβ) peptides may also mediate a wide range of nonpathogenic processes. Autophagy has been implicated in Aβ-mediated effects, although its precise function in neural differentiation remains unknown. Here, we ... ...

Abstract	Although regarded as neurotoxic, amyloid β (Aβ) peptides may also mediate a wide range of nonpathogenic processes. Autophagy has been implicated in Aβ-mediated effects, although its precise function in neural differentiation remains unknown. Here, we addressed the role of different Aβ fragments in neural stem cell (NSC) proliferation and differentiation, and investigated whether autophagy is involved in Aβ-induced alterations of neural fate. Our results demonstrate that neuronal and glial-specific protein markers are significantly induced by both Aβ1-40 and Aβ1-42. However, Aβ1-40 preferentially enhances neurogenesis of NSCs, as determined by βIII-tubulin, NeuN, and MAP2 neuronal marker immunoreactivity, while Aβ1-42 appears to favor gliogenesis. In contrast, Aβ25-35 does not influence NSC fate. The effect of Aβ1-40 on neurogenesis is partially dependent on its role in NSC self-renewal as both S-phase of the cell cycle and BrdU labeling were markedly increased. Nevertheless, Aβ1-40 resulted also in increased Tuj1 promoter activity. Autophagy, assessed by conversion of endogenous LC3-I/II, fluorescence of pGFP-LC3-transfected cells, and Atg9 protein levels, was evident in both Aβ1-40- and Aβ1-42-treated NSCs, independently of reactive oxygen species production and apoptosis. Finally, inhibition of autophagy by pharmacologic means abrogated Aβ-induced lineage-specific protein markers. These results support distinct roles for different Aβ peptides in NSC fate decision and underline the importance of autophagy control of this process.
MeSH term(s)	Adenine/analogs & derivatives ; Adenine/pharmacology ; Amyloid beta-Peptides/pharmacology ; Animals ; Astrocytes/cytology ; Astrocytes/drug effects ; Astrocytes/metabolism ; Autophagy/drug effects ; Biomarkers/metabolism ; Cell Differentiation/drug effects ; Cell Line ; Cell Lineage/drug effects ; Cell Proliferation/drug effects ; Cell Separation ; Fetus/cytology ; Mice ; Neural Stem Cells/cytology ; Neural Stem Cells/drug effects ; Neural Stem Cells/metabolism ; Neurons/cytology ; Neurons/drug effects ; Neurons/metabolism ; Prosencephalon/cytology ; Prosencephalon/embryology ; S Phase/drug effects
Chemical Substances	Amyloid beta-Peptides ; Biomarkers ; 3-methyladenine (5142-23-4) ; Adenine (JAC85A2161)
Language	English
Publishing date	2013-06-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-013-8471-1
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Article: Phenotypic screening identifies a new oxazolone inhibitor of necroptosis and neuroinflammation.

Oliveira, Sara R / Dionísio, Pedro A / Brito, Hugo / Franco, Lídia / Rodrigues, Catarina A B / Guedes, Rita C / Afonso, Carlos A M / Amaral, Joana D / Rodrigues, Cecília M P

Cell death discovery

2018 Volume 4, Page(s) 10

Abstract: Necroptosis is a regulated form of necrosis, which may be critical in the pathogenesis of neurodegenerative diseases. Neuroinflammation, characterized by the activation of glial cells such as microglia, is closely linked with neurodegenerative pathways ... ...

Abstract	Necroptosis is a regulated form of necrosis, which may be critical in the pathogenesis of neurodegenerative diseases. Neuroinflammation, characterized by the activation of glial cells such as microglia, is closely linked with neurodegenerative pathways and constitutes a major mechanism of neural damage and disease progression. Importantly, inhibition of necroptosis results in disease improvement, unveiling an alternative approach for therapeutic intervention. In the present study, we screened a small library of new molecules, potentially inhibitors of necroptosis, using two cellular models of necroptosis. A new oxazolone, Oxa12, reduced tumour necrosis factor α (TNF-α)-induced necroptosis in mouse L929 fibrosarcoma cells. Notably, Oxa12 strongly inhibited zVAD-fmk-induced necroptosis in murine BV2 microglial cells. Moreover, Oxa12 blocked phosphorylation of mixed-lineage kinase domain-like protein (MLKL), and interfered with necrosome complex formation, indicating that Oxa12 targets components upstream of MLKL. In fact, in silico molecular docking studies revealed that Oxa12 is occupying a region similar to the 1-aminoisoquinoline type II kinase inhibitor inside the receptor-interacting protein 1 (RIP1) kinase domain. Finally, in microglial cells, Oxa12 attenuated zVAD-fmk- and lipopolysaccharide (LPS)-induced inflammatory processes, as revealed by a marked decrease of TNF-α and/or IL-1β expression. More specifically, Oxa12 negatively targeted c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways, as well as NF-κB activation. Overall, we identified a strong lead inhibitor of necroptosis that is also effective at reducing inflammation-associated events. Oxa12 is a promising candidate molecule for further development to target disease states dependent on RIP kinase activity.
Language	English
Publishing date	2018-07-10
Publishing country	United States
Document type	Journal Article
ISSN	2058-7716
ISSN	2058-7716
DOI	10.1038/s41420-018-0067-0
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Article ; Online: Amyloid-β pathology is attenuated by tauroursodeoxycholic acid treatment in APP/PS1 mice after disease onset.

Dionísio, Pedro A / Amaral, Joana D / Ribeiro, Maria F / Lo, Adrian C / D'Hooge, Rudi / Rodrigues, Cecília M P

Neurobiology of aging

2015 Volume 36, Issue 1, Page(s) 228–240

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder hallmarked by the accumulation of extracellular amyloid-β (Aβ) peptide and intraneuronal hyperphosphorylated tau, as well as chronic neuroinflammation. Tauroursodeoxycholic acid (TUDCA) is an ... ...

Abstract	Alzheimer's disease (AD) is a neurodegenerative disorder hallmarked by the accumulation of extracellular amyloid-β (Aβ) peptide and intraneuronal hyperphosphorylated tau, as well as chronic neuroinflammation. Tauroursodeoxycholic acid (TUDCA) is an endogenous anti-apoptotic bile acid with potent neuroprotective properties in several experimental models of AD. We have previously reported the therapeutic efficacy of TUDCA treatment before amyloid plaque deposition in APP/PS1 double-transgenic mice. In the present study, we evaluated the protective effects of TUDCA when administrated after the onset of amyloid pathology. APP/PS1 transgenic mice with 7 months of age were injected intraperitoneally with TUDCA (500 mg/kg) every 3 days for 3 months. TUDCA treatment significantly attenuated Aβ deposition in the brain, with a concomitant decrease in Aβ₁₋₄₀ and Aβ₁₋₄₂ levels. The amyloidogenic processing of amyloid precursor protein was also reduced, indicating that TUDCA interferes with Aβ production. In addition, TUDCA abrogated GSK3β hyperactivity, which is highly implicated in tau hyperphosphorylation and glial activation. This effect was likely dependent on the specific activation of the upstream kinase, Akt. Finally, TUDCA treatment decreased glial activation and reduced proinflammatory cytokine messenger RNA expression, while partially rescuing synaptic loss. Overall, our results suggest that TUDCA is a promising therapeutic strategy not only for prevention but also for treatment of AD after disease onset.
MeSH term(s)	Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Alzheimer Disease/prevention & control ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Animals ; Cholagogues and Choleretics ; Cytokines/genetics ; Cytokines/metabolism ; Disease Models, Animal ; Gene Expression/drug effects ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Inflammation Mediators/metabolism ; Mice, Transgenic ; Molecular Targeted Therapy ; Neuroprotective Agents ; Presenilin-1/genetics ; Protein Aggregation, Pathological/drug therapy ; Protein Aggregation, Pathological/genetics ; Protein Aggregation, Pathological/pathology ; Protein Aggregation, Pathological/prevention & control ; RNA, Messenger/metabolism ; Taurochenodeoxycholic Acid/administration & dosage ; Taurochenodeoxycholic Acid/pharmacology ; tau Proteins/metabolism
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Cholagogues and Choleretics ; Cytokines ; Inflammation Mediators ; Mapt protein, mouse ; Neuroprotective Agents ; Presenilin-1 ; RNA, Messenger ; presenilin 1, mouse ; tau Proteins ; Taurochenodeoxycholic Acid (516-35-8) ; tauroursodeoxycholic acid (60EUX8MN5X) ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; Gsk3b protein, mouse (EC 2.7.11.1) ; Glycogen Synthase Kinase 3 (EC 2.7.11.26)
Language	English
Publishing date	2015-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604505-4
ISSN	1558-1497 ; 0197-4580
ISSN (online)	1558-1497
ISSN	0197-4580
DOI	10.1016/j.neurobiolaging.2014.08.034
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Article ; Online: MicroRNA-34a Modulates Neural Stem Cell Differentiation by Regulating Expression of Synaptic and Autophagic Proteins.

Morgado, Ana L / Xavier, Joana M / Dionísio, Pedro A / Ribeiro, Maria F C / Dias, Raquel B / Sebastião, Ana M / Solá, Susana / Rodrigues, Cecília M P

Molecular neurobiology

2014 Volume 51, Issue 3, Page(s) 1168–1183

Abstract: We have previously demonstrated the involvement of specific apoptosis-associated microRNAs (miRNAs), including miR-34a, in mouse neural stem cell (NSC) differentiation. In addition, a growing body of evidence points to a critical role for autophagy ... ...

Abstract	We have previously demonstrated the involvement of specific apoptosis-associated microRNAs (miRNAs), including miR-34a, in mouse neural stem cell (NSC) differentiation. In addition, a growing body of evidence points to a critical role for autophagy during neuronal differentiation, as a response-survival mechanism to limit oxidative stress and regulate synaptogenesis associated with this process. The aim of this study was to further investigate the precise role of miR-34a during NSC differentiation. Our results showed that miR-34a expression was markedly downregulated during neurogenesis. Neuronal differentiation and cell morphology, synapse function, and electrophysiological maturation were significantly impaired in miR-34a-overexpressing NSCs. In addition, synaptotagmin 1 (Syt1) and autophagy-related 9a (Atg9a) significantly increased during neurogenesis. Pharmacological inhibition of autophagy impaired both neuronal differentiation and cell morphology. Notably, we showed that Syt1 and Atg9a are miR-34a targets in neural differentiation context, markedly decreasing after miR-34a overexpression. Syt1 overexpression and rapamycin-induced autophagy partially rescued the impairment of neuronal differentiation by miR-34a. In conclusion, our results demonstrate a novel role for miR-34a regulation of NSC differentiation, where miR-34a downregulation and subsequent increase of Syt1 and Atg9a appear to be crucial for neurogenesis progression.
MeSH term(s)	Animals ; Autophagy/physiology ; Autophagy-Related Proteins ; Cell Differentiation/physiology ; Gene Expression Regulation ; Membrane Proteins/biosynthesis ; Mice ; MicroRNAs/physiology ; Neural Stem Cells/metabolism ; Prosencephalon/cytology ; Prosencephalon/metabolism ; Synapses/metabolism ; Synaptotagmin I/biosynthesis ; Vesicular Transport Proteins/biosynthesis
Chemical Substances	Atg9A protein, mouse ; Autophagy-Related Proteins ; MIRN34a microRNA, mouse ; Membrane Proteins ; MicroRNAs ; Synaptotagmin I ; Syt1 protein, mouse ; Vesicular Transport Proteins
Language	English
Publishing date	2014-06-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-014-8794-6
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