A Matrigel-based 3D construct of SH-SY5Y cells models the α-synuclein pathologies of Parkinson's disease

Li, Zhao-Feng; Cui, Lei; Jin, Mi-Mi; Hu, Dongyan; Hou, X.; Liu, Shushu; Zhang, Xiong; Zhu, Jian-Hong

doi:10.1242/dmm.049125

Cited by 10 publications

(4 citation statements)

References 66 publications

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“…This may suggest that α-syn is present as a protein aggregate within GBM cells, as reported in recent findings. These studies showed that the α-syn molecules that are still detectable after PK digestion correspond to aggregated α-syn [84]. This latter study, using 2D and 3D analyses of α-syn in cell cultures, showed that cytosol α-syn aggregates are mostly proteinase K (PK)-resistant.…”

Section: Discussionmentioning

confidence: 93%

Occurrence of Total and Proteinase K-Resistant Alpha-Synuclein in Glioblastoma Cells Depends on mTOR Activity

Ryskalin

Ferese

Morucci

et al. 2022

Cancers

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Alpha-synuclein (α-syn) is a protein considered to be detrimental in a number of degenerative disorders (synucleinopathies) of which α-syn aggregates are considered a pathological hallmark. The clearance of α-syn strongly depends on autophagy, which can be stimulated by inhibiting the mechanistic target of rapamycin (mTOR). Thus, the overexpression of mTOR and severe autophagy suppression may produce α-syn accumulation, including the proteinase K-resistant protein isoform. Glioblastoma multiforme (GBM) is a lethal brain tumor that features mTOR overexpression and severe autophagy inhibition. Cell pathology in GBM is reminiscent of a fast, progressive degenerative disorder. Therefore, the present work questions whether, as is analogous to neurons during degenerative disorders, an overexpression of α-syn occurs within GBM cells. A high amount of α-syn was documented in GBM cells via real-time PCR (RT-PCR), Western blotting, immunohistochemistry, immuno-fluorescence, and ultrastructural stoichiometry, compared with the amount of β- and γ-synucleins and compared with the amount of α-syn counted within astrocytes. The present study indicates that (i) α-syn is overexpressed in GBM cells, (ii) α-syn expression includes a proteinase-K resistant isoform, (iii) α-syn is dispersed from autophagy-like vacuoles to the cytosol, (iv) α-syn overexpression and cytosol dispersion are mitigated by rapamycin, and (v) the α-syn-related GBM-like phenotype is mitigated by silencing the SNCA gene.

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Section: Discussionmentioning

confidence: 93%

Occurrence of Total and Proteinase K-Resistant Alpha-Synuclein in Glioblastoma Cells Depends on mTOR Activity

Ryskalin

Ferese

Morucci

et al. 2022

Cancers

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“…Most of the studies analyzed in this review regarding neurodegenerative diseases employ the neuroblastoma SH-SY5Y cell line to develop 3D models where cells are differentiated into mature neurons. The efforts are directed at creating more in vivo-like models to better understand features of neurodegenerative diseases [ 50 , 51 , 52 , 54 , 57 ], pathogenesis [ 53 ] and treatment effects [ 60 , 61 ]. Some investigations are focused on the optimization of the differentiation protocols, and assess the capability for obtaining differentiated cells with electrically active behavior [ 58 , 59 , 62 , 63 , 90 ].…”

Section: Discussionmentioning

confidence: 99%

Advanced 3D Models of Human Brain Tissue Using Neural Cell Lines: State-of-the-Art and Future Prospects

Fabbri

Cacopardo

Ahluwalia

et al. 2023

Cells

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Human-relevant three-dimensional (3D) models of cerebral tissue can be invaluable tools to boost our understanding of the cellular mechanisms underlying brain pathophysiology. Nowadays, the accessibility, isolation and harvesting of human neural cells represents a bottleneck for obtaining reproducible and accurate models and gaining insights in the fields of oncology, neurodegenerative diseases and toxicology. In this scenario, given their low cost, ease of culture and reproducibility, neural cell lines constitute a key tool for developing usable and reliable models of the human brain. Here, we review the most recent advances in 3D constructs laden with neural cell lines, highlighting their advantages and limitations and their possible future applications.

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“…Total RNA was extracted using RNAiso Plus (9108, Takara) based on the manufacturer's protocol. RNA sequencing was performed by using the Illumina HiSeq X10 system at LC Sciences (Hangzhou, China) as previously described (46). After removing low-quality reads, HISAT package was used to map the reads to the Mus musculus reference genome (http://genome.ucsc.edu/).…”

Section: Rna Sequencingmentioning

confidence: 99%

SELENOT regulates endoplasmic reticulum calcium flux via SERCA2 and maintains dopaminergic DAT to protect against attention deficit hyperactivity disorder in mice

Guo,

Li,

et al. 2023

Preprint

Self Cite

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Attention deficit and hyperactivity disorder (ADHD) is a prevalent developmental disorder. SELENOT is an endoplasmic reticulum-resident selenocysteine-containing protein. We aimed to investigate the role of SELENOT in dopaminergic neurons. Results fromSelenotfl/fl;Dat-cremice showed that SELENOT deficiency in dopaminergic neurons resulted in ADHD-like behaviors including hyperlocomotion, recognition memory deficit, repetitive movement, and impulsivity. Dopamine metabolism, extrasynaptic dopamine, spontaneous excitatory postsynaptic currents in the striatum and electroencephalogram theta power were enhanced inSelenotfl/fl;Dat-cremice, whereas dopaminergic neurons in the substantia nigra were slightly reduced but exhibited normal neuronal firing and little cellular stress. Among dopamine- associated proteins, dopamine transporter (DAT) level was remarkably reduced and monoamine oxidase A increased mildly in the striatum and/or midbrain ofSelenotfl/fl;Dat-cremice. The ADHD-like phenotype and DAT ablation were corroborated inSelenotfl/fl;Nestin- cremice, but not inSelenotfl/fl;Gfap-cremice. In vitro overexpression and knockdown analyses and RNA-sequencing data revealed that SELENOT causatively regulated DAT mRNA and protein expression through Ca2+signaling and NURR1. SELENOT maintained cellular Ca2+levels via interaction with endoplasmic reticulum SERCA2, but not IP3Rs and RYRs, as demonstrated by Ca2+imaging, co-immunoprecipitation coupled with mass spectrometry, and colocalization analyses. Treatment with psychostimulants, amphetamine or methylphenidate, rescued the hyperactivity inSelenotfl/fl;Dat-cremice. In conclusion, SELENOT in dopaminergic neurons is indispensable to maintain proper dopamine signaling in the midbrain against ADHD.

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A Matrigel-based 3D construct of SH-SY5Y cells models the α-synuclein pathologies of Parkinson's disease

Cited by 10 publications

References 66 publications

Occurrence of Total and Proteinase K-Resistant Alpha-Synuclein in Glioblastoma Cells Depends on mTOR Activity

Occurrence of Total and Proteinase K-Resistant Alpha-Synuclein in Glioblastoma Cells Depends on mTOR Activity

Advanced 3D Models of Human Brain Tissue Using Neural Cell Lines: State-of-the-Art and Future Prospects

SELENOT regulates endoplasmic reticulum calcium flux via SERCA2 and maintains dopaminergic DAT to protect against attention deficit hyperactivity disorder in mice

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