title: Mislocalization of neuronal mitochondria reveals regulation of Wallerian degeneration and NMNAT/WLD(S)-mediated axon protection independent of axonal mitochondria.
abstract: Axon degeneration is a common and often early feature of neurodegeneration that correlates with the clinical manifestations and progression of neurological disease. Nicotinamide mononucleotide adenylytransferase (NMNAT) is a neuroprotective factor that delays axon degeneration following injury and in models of neurodegenerative diseases suggesting a converging molecular pathway of axon self-destruction. The underlying mechanisms have been under intense investigation and recent reports suggest a central role for axonal mitochondria in both degeneration and NMNAT/WLD(S) (Wallerian degeneration slow)-mediated protection. We used dorsal root ganglia (DRG) explants and Drosophila larval motor neurons (MNs) as models to address the role of mitochondria in Wallerian degeneration (WD). We find that expression of Drosophila NMNAT delays WD in human DRG neurons demonstrating evolutionary conservation of NMNAT function. Morphological comparison of mitochondria from WLD(S)-protected axons demonstrates that mitochondria shrink post-axotomy, though analysis of complex IV activity suggests that they retain their functional capacity despite this morphological change. To determine whether mitochondria are a critical site of regulation for WD, we genetically ablated mitochondria from Drosophila MN axons via the mitochondria trafficking protein milton. Milton loss-of-function did not induce axon degeneration in Drosophila larval MNs, and when axotomized WD proceeded stereotypically in milton distal axons although with a mild, but significant delay. Remarkably, the protective effects of NMNAT/WLD(S) were also maintained in axons devoid of mitochondria. These experiments unveil an axon self-destruction cascade governing WD that is not initiated by axonal mitochondria and for the first time illuminate a mitochondria-independent mechanism(s) regulating WD and NMNAT/WLD(S)-mediated axon protection.
authors: Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, FL 33136, USA.
authors: Brandon M
authors: BM
authors: Kitay
authors: Ryan
authors: R
authors: McCormack
authors: Yunfang
authors: Y
authors: Wang
authors: Pantelis
authors: P
authors: Tsoulfas
authors: R Grace
authors: RG
authors: Zhai
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D019771:Axotomy; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics; D057180:Frontotemporal Dementia / Q000235:genetics / Q000473:pathology; D005727:Ganglia, Spinal / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics / Q000378:metabolism*; D014855:Wallerian Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C470348:milt protein, Drosophila; C510972:Nmnat1 protein, mouse