title: The Neuronal Kinesin UNC-104/KIF1A Is a Key Regulator of Synaptic Aging and Insulin Signaling-Regulated Memory.
abstract: Aging is the greatest risk factor for a number of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Furthermore, normal aging is associated with a decline in sensory, motor, and cognitive functions. Emerging evidence suggests that synapse alterations, rather than neuronal cell death, are the causes of neuronal dysfunctions in normal aging and in early stages of neurodegenerative diseases. However, little is known about the mechanisms underlying age-related synaptic decline. Here, we uncover a surprising role of the anterograde molecular motor UNC-104/KIF1A as a key regulator of neural circuit deterioration in aging C. elegans. Through analyses of synapse protein localization, synaptic transmission, and animal behaviors, we find that reduced function of UNC-104 accelerates motor circuit dysfunction with age, whereas upregulation of UNC-104 significantly improves motor function at advanced ages and also mildly extends lifespan. In addition, UNC-104-overexpressing animals outperform wild-type controls in associative learning and memory tests. Further genetic analyses suggest that UNC-104 functions downstream of the DAF-2-signaling pathway and is regulated by the FOXO transcription factor DAF-16, which contributes to the effects of DAF-2 in neuronal aging. Together, our cellular, electrophysiological, and behavioral analyses highlight the importance of axonal transport in the maintenance of synaptic structural integrity and function during aging and raise the possibility of targeting kinesins to slow age-related neural circuit dysfunction.
authors.affiliation: Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Ling-Bo
authors.initials: LB
authors.lastname: Li
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; College of Life Science and Technology, Huazhong University of Science Technology, Wuhan, Hubei 430074, China.
authors.forename: Haoyun
authors.initials: H
authors.lastname: Lei
authors.affiliation: Department of Molecular Biology and LSI Genomics, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Rachel N
authors.initials: RN
authors.lastname: Arey
authors.affiliation: Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Pengpeng
authors.initials: P
authors.lastname: Li
authors.affiliation: College of Life Science and Technology, Huazhong University of Science Technology, Wuhan, Hubei 430074, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Molecular Biology and LSI Genomics, Princeton University, Princeton, NJ 08544, USA. Electronic address: ctmurphy@princeton.edu.
authors.forename: Coleen T
authors.initials: CT
authors.lastname: Murphy
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: shawnxu@umich.edu.
authors.forename: X Z Shawn
authors.initials: XZ
authors.lastname: Xu
authors.affiliation: Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: kangshen@stanford.edu.
authors.forename: Kang
authors.initials: K
authors.lastname: Shen
mesh_terms: D000375:Aging; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008568:Memory; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; C423186:UNC-104 protein, C elegans