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| Content Provider | Springer Nature : BioMed Central |
|---|---|
| Author | Kaur, Bhavneet Sharma, Pradeep Kumar Chatterjee, Barun Bissa, Bhawana Nattarayan, Vasugi Ramasamy, Soundhar Bhat, Ajay Lal, Megha Samaddar, Sarbani Banerjee, Sourav Roy, Soumya Sinha |
| Abstract | Homocysteine (Hcy), produced physiologically in all cells, is an intermediate metabolite of methionine and cysteine metabolism. Hyperhomocysteinemia (HHcy) resulting from an in-born error of metabolism that leads to accumulation of high levels of Hcy, is associated with vascular damage, neurodegeneration and cognitive decline. Using a HHcy model in neuronal cells, primary cortical neurons and transgenic zebrafish, we demonstrate diminished autophagy and Hcy-induced neurotoxicity associated with mitochondrial dysfunction, fragmentation and apoptosis. We find this mitochondrial dysfunction is due to Hcy-induced proteotoxicity leading to ER stress. We show this sustained proteotoxicity originates from the perturbation of upstream autophagic pathways through an aberrant activation of mTOR and that protetoxic stress act as a feedforward cues to aggravate a sustained ER stress that culminate to mitochondrial apoptosis in HHcy model systems. Using chemical chaperones to mitigate sustained ER stress, Hcy-induced proteotoxicity and consequent neurotoxicity were rescued. We also rescue neuronal lethality by activation of autophagy and thereby reducing proteotoxicity and ER stress. Our findings pave the way to devise new strategies for the treatment of neural and cognitive pathologies reported in HHcy, by either activation of upstream autophagy or by suppression of downstream ER stress. Video Abstract |
| Related Links | https://biosignaling.biomedcentral.com/counter/pdf/10.1186/s12964-023-01288-w.pdf |
| Ending Page | 23 |
| Page Count | 23 |
| Starting Page | 1 |
| File Format | HTM / HTML |
| DOI | 10.1186/s12964-023-01288-w |
| Journal | Cell Communication and Signaling |
| Issue Number | 1 |
| Volume Number | 21 |
| Language | English |
| Publisher | BioMed Central |
| Publisher Date | 2023-09-25 |
| Access Restriction | Open |
| Subject Keyword | Cell Biology Protein-Ligand Interactions Receptors Cytokines and Growth Factors Homocysteine Hyperhomocysteinemia CBS Neuron Autophagy Endoplasmic reticulum Mitochondria Apoptosis |
| Content Type | Text |
| Resource Type | Article |
| Subject | Biochemistry Cell Biology Molecular Biology |
| Journal Impact Factor | 8.2/2023 |
| 5-Year Journal Impact Factor | 8/2023 |
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