Article ; Online: N-Acetyltransferase 9 ameliorates Aβ42-mediated neurodegeneration in the Drosophila eye.
2023 Volume 14, Issue 7, Page(s) 478
Abstract: Alzheimer's disease (AD), a progressive neurodegenerative disorder, manifests as accumulation of amyloid-beta-42 (Aβ42) plaques and intracellular accumulation of neurofibrillary tangles (NFTs) that results in microtubule destabilization. Targeted ... ...
| Abstract | Alzheimer's disease (AD), a progressive neurodegenerative disorder, manifests as accumulation of amyloid-beta-42 (Aβ42) plaques and intracellular accumulation of neurofibrillary tangles (NFTs) that results in microtubule destabilization. Targeted expression of human Aβ42 (GMR > Aβ42) in developing Drosophila eye retinal neurons results in Aβ42 plaque(s) and mimics AD-like extensive neurodegeneration. However, there remains a gap in our understanding of the underlying mechanism(s) for Aβ42-mediated neurodegeneration. To address this gap in information, we conducted a forward genetic screen, and identified N-acetyltransferase 9 (Mnat9) as a genetic modifier of GMR > Aβ42 neurodegenerative phenotype. Mnat9 is known to stabilize microtubules by inhibiting c-Jun-N- terminal kinase (JNK) signaling. We found that gain-of-function of Mnat9 rescues GMR > Aβ42 mediated neurodegenerative phenotype whereas loss-of-function of Mnat9 exhibits the converse phenotype of enhanced neurodegeneration. Here, we propose a new neuroprotective function of Mnat9 in downregulating the JNK signaling pathway to ameliorate Aβ42-mediated neurodegeneration, which is independent of its acetylation activity. Transgenic flies expressing human NAT9 (hNAT9), also suppresses Aβ42-mediated neurodegeneration thereby suggesting functional conservation in the interaction of fly Mnat9 or hNAT9 with JNK-mediated neurodegeneration. These studies add to the repertoire of molecular mechanisms that mediate cell death response following accumulation of Aβ42 and may provide new avenues for targeting neurodegeneration. |
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| MeSH term(s) | Animals ; Humans ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/genetics ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Drosophila/genetics ; Drosophila/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Peptide Fragments/metabolism ; JNK Mitogen-Activated Protein Kinases ; Acetyltransferases |
| Chemical Substances | Amyloid beta-Peptides ; amyloid beta-protein (1-42) ; Peptide Fragments ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Acetyltransferases (EC 2.3.1.-) |
| Language | English |
| Publishing date | 2023-07-28 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; 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/s41419-023-05973-z |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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