D-Cysteine Activates Chaperone-Mediated Autophagy in Cerebellar Purkinje Cells via the Generation of Hydrogen Sulfide and Nrf2 Activation

Ueda, Erica; Ohta, Tomoko; Konno, Ayumu; Hirai, Hirokazu; Kurauchi, Yuki; Katsuki, Hiroshi; Seki, Takahiro

doi:10.3390/cells11071230

Cited by 3 publications

(1 citation statement)

References 65 publications

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“…Besides, the loss of Purkinje cells may be caused by a series of changes in transcription factors, which may involve downstream gene imbalance leading to abnormal protein folding modi cation [43], activation of apoptosis [44], and an increase in nutritional neurons such as astrocytes [45]. In addition, the absence of transcription factors related to Purkinje cell development can also cause endoplasmic reticulum stress [46], abnormal expression of signaling proteins in related pathways [47], and a series of molecular changes. Our research on these mechanistic pathways is still insu cient, but our preliminary exploration of the speci city of KLF15 in the neural eld is innovative.…”

Section: Discussionmentioning

confidence: 99%

Distribution and Functional Significance of KLF15 in Mouse Cerebellum

Li,

Cao,

Chen

et al. 2024

Preprint

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Kruppel-like factor 15 (KLF15), a member of the KLF family, is closely involved in many biological processes. However, the mechanism by which KLF15 regulates neural development is still unclear. Considering the complexity and importance of neural network development, in this study, we investigated the potent regulatory role of KLF15 in neural network development. KLF15 was detected highly expressed in the cerebellum and enriched in Purkinje cells, with a significant increase in KLF15 expression between 15–20 days of neural development. Knockdown of KLF15 led to loss of Purkinje cells and impaired motility in mice. Therefore, our study aims to elucidate the relationship between KLF15 and Purkinje cells in mice, may provide a new research idea for the developmental mechanism of the mouse cerebellum.

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Section: Discussionmentioning

confidence: 99%

Distribution and Functional Significance of KLF15 in Mouse Cerebellum

Li,

Cao,

Chen

et al. 2024

Preprint

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Nurr1 overexpression in the primary motor cortex alleviates motor dysfunction induced by intracerebral hemorrhage in the striatum in mice

Kinoshita,

Motomura,

Ushida

et al. 2024

Neurotherapeutics

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Identification of a novel aromatic-turmerone analog that activates chaperone-mediated autophagy through the persistent activation of p38

Motomura,

Ueda,

Boateng

et al. 2024

Front. Cell Dev. Biol.

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Introduction: Aromatic (Ar)-turmerone is a bioactive component of turmeric oil obtained from Curcuma longa. We recently identified a novel analog (A2) of ar-turmerone that protects dopaminergic neurons from toxic stimuli by activating nuclear factor erythroid 2-related factor 2 (Nrf2). D-cysteine increases Nrf2, leading to the activation of chaperone-mediated autophagy (CMA), a pathway in the autophagy-lysosome protein degradation system, in primary cultured cerebellar Purkinje cells. In this study, we attempted to identify novel analogs of ar-turmerone that activate Nrf2 more potently and investigated whether these analogs activate CMA.Methods: Four novel analogs (A4–A7) from A2 were synthesized. We investigated the effects of A2 and novel 4 analogs on Nrf2 expression via immunoblotting and CMA activity via fluorescence observation.Results: Although all analogs, including A2, increased Nrf2 expression, only A4 activated CMA in SH-SY5Y cells. Additionally, A4-mediated CMA activation was not reversed by Nrf2 inhibition, indicating that A4 activated CMA via mechanisms other than Nrf2 activation. We focused on p38, which participates in CMA activation. Inhibition of p38 significantly prevented A4-mediated activation of CMA. Although all novel analogs significantly increased the phosphorylation of p38 6 h after drug treatment, only A4 significantly increased phosphorylation 24 h after treatment. Finally, we revealed that A4 protected SH-SY5Y cells from the cytotoxicity of rotenone, and that this protection was reversed by inhibiting p38.Conclusion: These findings suggest that the novel ar-turmerone analog, A4, activates CMA and protects SH-SY5Y cells through the persistent activation of p38.

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D-Cysteine Activates Chaperone-Mediated Autophagy in Cerebellar Purkinje Cells via the Generation of Hydrogen Sulfide and Nrf2 Activation

Cited by 3 publications

References 65 publications

Distribution and Functional Significance of KLF15 in Mouse Cerebellum

Distribution and Functional Significance of KLF15 in Mouse Cerebellum

Nurr1 overexpression in the primary motor cortex alleviates motor dysfunction induced by intracerebral hemorrhage in the striatum in mice

Identification of a novel aromatic-turmerone analog that activates chaperone-mediated autophagy through the persistent activation of p38

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