title: Pathogenesis of autosomal dominant hereditary spastic paraplegia (SPG6) revealed by a rat model.
abstract: Hereditary spastic paraplegias (HSPs) are characterized by progressive spasticity and weakness in the lower extremities that result from length-dependent central to peripheral axonal degeneration. Mutations in the non-imprinted Prader-Willi/Angelman syndrome locus 1 (NIPA1) transmembrane protein cause an autosomal dominant form of HSP (SPG6). Here, we report that transgenic (Tg) rats expressing a human NIPA1/SPG6 mutation in neurons (Thy1.2-hNIPA1) show marked early onset behavioral and electrophysiologic abnormalities. Detailed morphologic analyses reveal unique histopathologic findings, including the accumulation of tubulovesicular organelles with endosomal features that start at axonal and dendritic terminals, followed by multifocal vacuolar degeneration in both the CNS and peripheral nerves. In addition, the NIPA1 mutation in the spinal cord from older Tg rats results in an increase in bone morphogenetic protein type II receptor expression, suggesting that its degradation is impaired. This Thy1.2-hNIPA1 Tg rat model may serve as a valuable tool for understanding endosomal trafficking in the pathogenesis of a subgroup of HSP with an abnormal interaction with bone morphogenetic protein type II receptor, as well as for developing potential therapeutic strategies for diseases with axonal degeneration and similar pathogenetic mechanisms.
authors.affiliation: From the Department of Neurology, The Ohio State University, Columbus, Ohio (FW, WDA, OG, HM, MS, AH, AH, ZS, YYK); The Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas (REH); Department of Pediatrics and Pathology, The Ohio State University/Nationwide Children's Hospital (ZS); and Center for Gene Therapy, The Research Institute, Nationwide Children's Hospital (ZS), Columbus, Ohio.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Watanabe
authors.forename: William D
authors.initials: WD
authors.lastname: Arnold
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.forename: Odelia
authors.initials: O
authors.lastname: Ghodsizadeh
authors.forename: Harmeet
authors.initials: H
authors.lastname: Moti
authors.forename: Mackenzie
authors.initials: M
authors.lastname: Schumer
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hashmi
authors.forename: Anthony
authors.initials: A
authors.lastname: Hernandez
authors.forename: Amita
authors.initials: A
authors.lastname: Sneh
authors.forename: Zarife
authors.initials: Z
authors.lastname: Sahenk
authors.forename: Yaz Y
authors.initials: YY
authors.lastname: Kisanuki
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D001522:Behavior, Animal / Q000502:physiology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D011992:Endosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009048:Motor Skills / Q000502:physiology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D055647:Rats, Transgenic; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D014617:Vacuoles / Q000378:metabolism / Q000473:pathology
chemical_list: D008565:Membrane Proteins; C478824:NIPA1 protein, human