title: Reducing Lissencephaly-1 levels augments mitochondrial transport and has a protective effect in adult Drosophila neurons.
abstract: Defective transport of mitochondria in axons is implicated in the pathogenesis of several age-associated neurodegenerative diseases. However, the regulation and function of axonal mitochondrial motility during normal ageing is poorly understood. Here, we use novel imaging procedures to characterise axonal transport of these organelles in the adult Drosophila wing nerve. During early adult life there is a boost and progressive decline in the proportion of mitochondria that are motile, which is not due to general changes in cargo transport. Experimental inhibition of the mitochondrial transport machinery specifically in adulthood accelerates the appearance of focal protein accumulations in ageing axons, which is suggestive of defects in protein homeostasis. Unexpectedly, lowering levels of Lissencephaly-1 (Lis1), a dynein motor co-factor, augments axonal mitochondrial transport in ageing wing neurons. Lis1 mutations suppress focal protein accumulations in ageing neurons, including those caused by interfering with the mitochondrial transport machinery. Our data provide new insights into the dynamics of mitochondrial motility in adult neurons in vivo, identify Lis1 as a negative regulator of transport of these organelles, and provide evidence of a link between mitochondrial movement and neuronal protein homeostasis.
authors.affiliation: Division of Cell Biology, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Alessio
authors.initials: A
authors.lastname: Vagnoni
authors.affiliation: Division of Cell Biology, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Hoffmann
authors.affiliation: Division of Cell Biology, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK sbullock@mrc-lmb.cam.ac.uk.
authors.forename: Simon L
authors.initials: SL
authors.lastname: Bullock
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D000066829:Neuroprotection; D011984:Sensory Receptor Cells / Q000378:metabolism; D014921:Wings, Animal / Q000166:cytology
chemical_list: D029721:Drosophila Proteins; C513192:Lis-1 protein, Drosophila; D008869:Microtubule-Associated Proteins
keywords: Axonal transport; Drosophila; Lissencephaly-1; Mitochondria