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.

Early glial activation, synaptic changes and axonal pathology in the thalamocortical system of Niemann–Pick type C1 mice

“…In human NPC disease, imaging studies have found that the thalamus amongst other structures has an altered signal compared to controls (Huang et al, 2011; Walterfang et al, 2010). Interestingly, there is evidence for selective pathology at multiple steps of sensory pathways in Npc1 −/− mice, with degeneration at the level of the sensory dorsal root ganglion (Ohara et al, 2004) and brain stem nuclei (Luan et al, 2008). Our data shows that the somatosensory thalamocortical pathway (VPM/VPL connecting to S1BF) displayed the most pronounced pathology, with the interconnected Po nucleus that also relays somatosensory input similarly displaying localised reactive gliosis (Table 1).…”

Anatomically Defined Neuron-Based Rescue of Neurodegenerative Niemann–Pick Type C Disorder

“…With the use of the tetO-Npc1-YFP transgenic mouse strain generated for this study, future studies can take advantage of gene delivery of a tTA transgene, or other existing mouse driver lines, to target the thalamus or other CNS areas affected in Npc1 −/− mice, such as the brainstem (Luan et al, 2008). The targeting of increasingly discrete neuronal networks and the development of assays to measure specific behaviors will be useful in order to associate rescue of a particular neural circuit with improvements to health-related quality of life, prolonged lifespan, and inhibition of neurological signs.…”

Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

“…The most striking consequence of NPC1 deficiency in the brains of mice and humans is a profound loss of Purkinje neurons in the cerebellum (103)(104)(105). In other regions of the brain, such as the cerebral cortex and thalamus, neuronal apoptosis also occurs but is less common than axonal swelling and ectopic dendrite formation ( 51,52,(106)(107)(108)(109). The reason why Purkinje neurons are the most sensitive neurons to NPC defi ciency is not clear ( 39 ).…”