| First Author | Zhang L | Year | 2022 |
| Journal | Oxid Med Cell Longev | Volume | 2022 |
| Pages | 8096009 | PubMed ID | 35116093 |
| Mgi Jnum | J:319748 | Mgi Id | MGI:6865015 |
| Doi | 10.1155/2022/8096009 | Citation | Zhang L, et al. (2022) Interaction between TRPML1 and p62 in Regulating Autophagosome-Lysosome Fusion and Impeding Neuroaxonal Dystrophy in Alzheimer's Disease. Oxid Med Cell Longev 2022:8096009 |
| abstractText | The loss of transient receptor potential mucolipin 1 (TRPML1), an endosomal and lysosomal Ca(2+)-releasing channel, has been implicated in neurodegenerative disorders. Mounting evidence have shown that TRPML1 could clear intraneuronal amyloid-beta (Abeta), which triggers a hypothesis that TRPML1 activation may be beneficial for axonal transport in Alzheimer's disease (AD). In this work, the functional roles of TRPML1 were studied in the APP/PS1 transgenic mice and Abeta1-42-stimulated hippocampal neurons HT22. We found that lentivirus-mediated overexpression of TRPML1 was shown to promote an accumulation of autolysosomes and increase brain-derived neurotrophic factor (BDNF) transportation to the nucleus, suggesting an axon-protective function. More importantly, we found that TRPML1 also increased p62 that interacted with dynein. Lentivirus-mediated knockdown of p62 or inhibition of dynein by ciliobrevin D stimulation was found to reduce autolysosome formation and nuclear accumulation of BDNF in HT22 cells with Abeta1-42 stimulation. Inhibition of p62 by XRK3F2 stimulation was observed to promote the death of hippocampal neurons of the APP/PS1 transgenic mice. TRPML1 recruited dynein by interacting with p62 to promote the autophagosome-lysosome fusion to mediate BDNF nuclear translocation to impede axon dystrophy in mice with Alzheimer-like phenotypes. In summary, these results demonstrate the presence of a TRPML1/p62/dynein regulatory network in AD, and activation of TRPML1 is required for axon protection to prevent neuroaxonal dystrophy. |
