title: Brainstem neuropathology in a mouse model of Niemann-Pick disease type C.
abstract: Niemann-Pick disease type C (NPC) is a neurovisceral lipid storage disorder characterized by progressive and widespread neurodegeneration. Although some characteristic symptoms of NPC result from brainstem dysfunction, little information is available about which brainstem structures are affected. In this study, the brainstems of mutant BALB/c NPC1-/- mice with a retroposon insertion in the NPC1 gene were examined for neuropathological changes. In the midbrain, the integrated optic density (IOD) and cell count density of tyrosine-hydroxylase (TH) immunostained neurons were decreased in the substantia nigra. In the pons, TH immunoreactivity in the locus ceruleus (LC) neurons was decreased, while the IOD and the neuronal density of choline acetyltransferase (ChAT)-immunostained neurons in the pedunculopontine tegmental nucleus were preserved. The ChAT immunoreactivity of the hypoglossal nucleus (12N) neurons was not decreased, but Klüver-Barrera staining showed that neuronal density in the nucleus of the solitary tract (NTS) was decreased. Klüver-Barrera and neuronal nuclei (NeuN) staining showed a decrease in neuronal density in the ventral cochlear nucleus, but not in the dorsal cochlear nucleus. Gliosis was widely identified by GFAP staining in various brainstem structures, including the superior and inferior colliculi, the rostral interstitial nucleus of the medial longitudinal fasciculus, the oculomotor complex, the medial geniculate nucleus, the nucleus ambiguus, and the 12N. However, GFAP expression was not augmented in the LC, the cochlear nucleus, or the NTS. These neuropathological findings suggest a basis for the neurological syndromes observed in NPC, such as rigidity, oculomotor symptoms, cataplexy and sleep disturbance, dysphagia, and perceptive deafness.
authors.affiliation: Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Japan. nicholasluan@gmail.com
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Luan
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Saito
authors.forename: Hajime
authors.initials: H
authors.lastname: Miyata
authors.forename: Eisaku
authors.initials: E
authors.lastname: Ohama
authors.forename: Haruaki
authors.initials: H
authors.lastname: Ninomiya
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics; D001933:Brain Stem / Q000473:pathology*; D002452:Cell Count; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000473:pathology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D014446:Tyrosine 3-Monooxygenase; D002795:Choline O-Acetyltransferase; D010751:Phosphopyruvate Hydratase