Amelioration of enteric neuropathology in a mouse model of Niemann‐Pick C by Npc1 expression in enteric glia

Kapur, Raj P.; Donohue, Carolyn; Jelínek, David; Erickson, Robert P.

doi:10.1002/jnr.22126

Cited by 16 publications

(15 citation statements)

References 26 publications

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“…In the CNS, NPC1 is expressed predominantly in perisynaptic astrocyte processes that are closely associated with nerve terminals, the earliest site of degeneration in the disease, suggesting that disruption of NPC1-mediated vesicular trafficking in astrocytes may be linked to neuronal degeneration [ 178 ]. It is interesting that selective restoration of expression of Npc1 in GFAP-positive astrocytes in Npc1 −/− mice enhanced survival and decreased neuronal storage of cholesterol in the CNS, while restoration of expression of Npc1 in GFAP-positive in enteric glial cells in Npc1 −/− mice ameliorated enteric neuropathology [ 110 , 265 ].…”

Section: Astrocyte Appearance and Roles In Cns Disorders And Pathologmentioning

confidence: 99%

Astrocytes: biology and pathology

2009

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Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to longlasting scar formation with rearrangement of tissue structure.Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.

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Section: Astrocyte Appearance and Roles In Cns Disorders And Pathologmentioning

confidence: 99%

Astrocytes: biology and pathology

2009

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“…Considerable disease correction was observed when functional NPC1 protein was produced in Npc1 −/− mice using a prion (Loftus et al, 2002) or a glial fibrillary acidic protein (GFAP) promoter-driven transgene (Donohue et al, 2009; Kapur et al, 2009; Zhang et al, 2008). The prion promoter directed high expression of Npc1 in the brain, both in neurons and glia (Loftus et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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

López¹,

Klein²,

Dimbil³

et al. 2011

J. Neurosci.

122

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Niemann-Pick type C disease is a fatal lysosomal storage disorder caused by loss of NPC1 function. The disorder severely affects multiple body systems, particularly the nervous system. To test whether rescue of NPC1 activity in neurons, astrocytes, or other cell types can correct the neurological defects, a Tet-inducible Npc1-YFP transgene was introduced into Npc1−/− mice for the cell type-specific rescue of NPC1 loss. NPC1-YFP produced in neurons prevented neuron degeneration, slowed reactive glial activity, and ameliorated the disease. NPC1-YFP produced in astrocytes or in cells of visceral tissue did not. These results suggest that loss of NPC1 activity from neurons is the primary cause of the neuropathology and that rescue of NPC1 function in neurons is sufficient to mitigate the disease. The ability of neurons to survive and function in a cell-autonomous fashion allowed the use of this newly engineered rescue system to further define the brain regions or neuron populations required to ameliorate a neurological symptom. NPC1-YFP produced specifically in cerebellar Purkinje neurons reduced ataxia, increased weight, and prolonged life, but it did not prevent the eventual decline and premature death of Npc1−/− mice. Significant increase in lifespan correlated with sustained reduction of inflammation in the thalamus. Neuron rescue of other forebrain areas provided little benefit. Future work targeting increasingly discrete neuronal networks should reveal which CNS areas are critical for survival. This work may have broad implications for understanding the anatomical and cellular basis of neurological signs and symptoms of other neurodegenerative and lysosomal disorders.

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“…These mice express Npc1 only in neurons or in neurons and fibrillary astrocytes and have significantly prolonged survivals [16,17]. The transgene is not expected to have any significant influence on lung function, although it does influence the intestine because of the presence of glia in enteric ganglia [27]. Mice were housed in temperature and humidity controlled rooms and NIH31 chow and water were available ad libitum.…”

Section: Methodsmentioning

confidence: 99%

Extensive macrophage accumulation in young and old Niemann–Pick C1 model mice involves the alternative, M2, activation pathway and inhibition of macrophage apoptosis

Deutsch

Muralidhar

et al. 2016

Gene

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We have studied the pathophysiology of lung disease which occurs in two mouse models of Niemann-Pick C1 disease. We utilized Npc1−/− mice transgenic for normal gene expression in glia or neurons and glia at ages several fold the usual and a mouse model of the juvenile form of NPC1, a point mutation, at one age to confirm some findings. Lung weights, as per cent of body weight, increase much more than liver and spleen weights. Although pulmonary function parameters only vary for hysteresis between young and older Npc1−/− mice, they are markedly different than those found in normal control mice. Cholesterol accumulation continued in the older mice but sphingosine-1-phosphate was not increased. Bronchoalveolar lavage (BAL) showed a massive increase (26X) in the number of macrophages. Histologic examination from the older, transgenic Npc1−/− mice showed small foci of alveolar proteinosis and evidence of hemorrhage, as well as dense macrophage accumulation. A large subset of macrophages was immunopositive for Fizz1 or arginase-1, markers of the alternative activation pathway, while no Fizz1 or arginase-1 positive macrophages were found in wild-type mice. The percentage of marker positive macrophages was relatively stable at 5–10% at various ages and within the 2 transgenic models. Phosphohistone H3 and Ki67 showed low levels of proliferation of these macrophages. Apoptosis was prominent within lung capillary endothelial cells, but limited within macrophages. Thus, activation of the alternative pathway is involved in Niemann-Pick C1 associated pulmonary macrophage accumulation, with low proliferation of these cells balanced by low levels of apoptosis.

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Amelioration of enteric neuropathology in a mouse model of Niemann‐Pick C by Npc1 expression in enteric glia

Cited by 16 publications

References 26 publications

Astrocytes: biology and pathology

Astrocytes: biology and pathology

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

Extensive macrophage accumulation in young and old Niemann–Pick C1 model mice involves the alternative, M2, activation pathway and inhibition of macrophage apoptosis

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