Open Close
Reference
Citation
Yoon, W.H., Sandoval, H., Nagarkar-Jaiswal, S., Jaiswal, M., Yamamoto, S., Haelterman, N.A., Putluri, N., Putluri, V., Sreekumar, A., Tos, T., Aksoy, A., Donti, T., Graham, B.H., Ohno, M., Nishi, E., Hunter, J., Muzny, D.M., Carmichael, J., Shen, J., Arboleda, V.A., Nelson, S.F., Wangler, M.F., Karaca, E., Lupski, J.R., Bellen, H.J. (2017). Loss of Nardilysin, a Mitochondrial Co-chaperone for α-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration.  Neuron 93(1): 115--131.
FlyBase ID
FBrf0234411
Publication Type
Research paper
Abstract
We previously identified mutations in Nardilysin (dNrd1) in a forward genetic screen designed to isolate genes whose loss causes neurodegeneration in Drosophila photoreceptor neurons. Here we show that NRD1 is localized to mitochondria, where it recruits mitochondrial chaperones and assists in the folding of α-ketoglutarate dehydrogenase (OGDH), a rate-limiting enzyme in the Krebs cycle. Loss of Nrd1 or Ogdh leads to an increase in α-ketoglutarate, a substrate for OGDH, which in turn leads to mTORC1 activation and a subsequent reduction in autophagy. Inhibition of mTOR activity by rapamycin or partially restoring autophagy delays neurodegeneration in dNrd1 mutant flies. In summary, this study reveals a novel role for NRD1 as a mitochondrial co-chaperone for OGDH and provides a mechanistic link between mitochondrial metabolic dysfunction, mTORC1 signaling, and impaired autophagy in neurodegeneration.
PubMed ID
PubMed Central ID
PMC5242142 (PMC) (EuropePMC)
Associated Information
Comments
Associated Files
Other Information
Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Neuron
    Title
    Neuron
    Publication Year
    1988-
    ISBN/ISSN
    0896-6273
    Data From Reference
    Aberrations (8)
    Alleles (38)
    Genes (69)
    Human Disease Models (2)
    Physical Interactions (61)
    Cell Lines (1)
    Natural transposons (2)
    Insertions (5)
    Experimental Tools (4)
    Transgenic Constructs (31)