Apoptosis accompanied by up-regulation of TNF-α death pathway genes in the brain of Niemann–Pick type C disease

2005 ◽  
Vol 84 (1) ◽  
pp. 9-17 ◽  
Author(s):  
Yun-Ping Wu ◽  
Hiroki Mizukami ◽  
Junko Matsuda ◽  
Yuko Saito ◽  
Richard L. Proia ◽  
...  
Keyword(s):  
Tnf Α ◽  
Type C ◽  
2021 ◽  
Vol 22 (16) ◽  
pp. 8858
Author(s):  
Antonietta Bernardo ◽  
Chiara De Nuccio ◽  
Sergio Visentin ◽  
Alberto Martire ◽  
Luisa Minghetti ◽  
...  

Niemann–Pick type C (NPC) disease is a wide-spectrum clinical condition classified as a neurovisceral disorder affecting mainly the liver and the brain. It is caused by mutations in one of two genes, NPC1 and NPC2, coding for proteins located in the lysosomes. NPC proteins are deputed to transport cholesterol within lysosomes or between late endosome/lysosome systems and other cellular compartments, such as the endoplasmic reticulum and plasma membrane. The first trait of NPC is the accumulation of unesterified cholesterol and other lipids, like sphingosine and glycosphingolipids, in the late endosomal and lysosomal compartments, which causes the blockade of autophagic flux and the impairment of mitochondrial functions. In the brain, the main consequences of NPC are cerebellar neurodegeneration, neuroinflammation, and myelin defects. This review will focus on myelin defects and the pivotal importance of cholesterol for myelination and will offer an overview of the molecular targets and the pharmacological strategies so far proposed, or an object of clinical trials for NPC. Finally, it will summarize recent data on a new and promising pharmacological perspective involving A2A adenosine receptor stimulation in genetic and pharmacological NPC dysmyelination models.


Neurology ◽  
2020 ◽  
Vol 94 (16) ◽  
pp. e1716-e1725
Author(s):  
Mark Walterfang ◽  
Maria A. Di Biase ◽  
Vanessa L. Cropley ◽  
Andrew M. Scott ◽  
Graeme O'Keefe ◽  
...  

ObjectiveTo test the hypothesis that neuroinflammation is a key process in adult Niemann-Pick type C (NPC) disease, we undertook PET scanning utilizing a ligand binding activated microglia on 9 patients and 9 age- and sex-matched controls.MethodWe scanned all participants with the PET radioligand 11C-(R)-PK-11195 and undertook structural MRI to measure gray matter volume and white matter fractional anisotropy (FA).ResultsWe found increased binding of 11C-(R)-PK-11195 in total white matter compared to controls (p < 0.01), but not in gray matter regions, and this did not correlate with illness severity or duration. Gray matter was reduced in the thalamus (p < 0.0001) in patients, who also showed widespread reductions in FA across the brain compared to controls (p < 0.001). A significant correlation between 11C-(R)-PK11195 binding and FA was shown (p = 0.002), driven by the NPC patient group.ConclusionsOur findings suggest that neuroinflammation—particularly in white matter—may underpin some structural and degenerative changes in patients with NPC.


2008 ◽  
Vol 50 (2) ◽  
pp. 327-333 ◽  
Author(s):  
Victoria M. Rimkunas ◽  
Mark J. Graham ◽  
Rosanne M. Crooke ◽  
Laura Liscum

2003 ◽  
Vol 200 (1) ◽  
pp. 104-111 ◽  
Author(s):  
Roland Distl ◽  
Stephanie Treiber-Held ◽  
Frank Albert ◽  
Volker Meske ◽  
Klaus Harzer ◽  
...  

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Larisa Kavetsky ◽  
Kayla K. Green ◽  
Bridget R. Boyle ◽  
Fawad A. K. Yousufzai ◽  
Zachary M. Padron ◽  
...  

Abstract Niemann Pick Type-C disease (NPC) is an inherited lysosomal storage disease (LSD) caused by pathogenic variants in the Npc1 or Npc2 genes that lead to the accumulation of cholesterol and lipids in lysosomes. NPC1 deficiency causes neurodegeneration, dementia and early death. Cerebellar Purkinje cells (PCs) are particularly hypersensitive to NPC1 deficiency and degenerate earlier than other neurons in the brain. Activation of microglia is an important contributor to PCs degeneration in NPC. However, the mechanisms by which activated microglia promote PCs degeneration in NPC are not completely understood. Here, we are demonstrating that in the Npc1nmf164 mouse cerebellum, microglia in the molecular layer (ML) are activated and contacting dendrites at early stages of NPC, when no loss of PCs is detected. During the progression of PCs degeneration in Npc1nmf164 mice, accumulation of phagosomes and autofluorescent material in microglia at the ML coincided with the degeneration of dendrites and PCs. Feeding Npc1nmf164 mice a western diet (WD) increased microglia activation and corresponded with a more extensive degeneration of dendrites but not PC somata. Together our data suggest that microglia contribute to the degeneration of PCs by interacting, engulfing and phagocytosing their dendrites while the cell somata are still present.


2020 ◽  
Vol 64 (3) ◽  
pp. 591-606 ◽  
Author(s):  
Emyr Lloyd-Evans ◽  
Helen Waller-Evans

Abstract Neurosteroids are steroid hormones synthesised de novo in the brain and peripheral nervous tissues. In contrast to adrenal steroid hormones that act on intracellular nuclear receptors, neurosteroids directly modulate plasma membrane ion channels and regulate intracellular signalling. This review provides an overview of the work that led to the discovery of neurosteroids, our current understanding of their intracellular biosynthetic machinery, and their roles in regulating the development and function of nervous tissue. Neurosteroids mediate signalling in the brain via multiple mechanisms. Here, we describe in detail their effects on GABA (inhibitory) and NMDA (excitatory) receptors, two signalling pathways of opposing function. Furthermore, emerging evidence points to altered neurosteroid function and signalling in neurological disease. This review focuses on neurodegenerative diseases associated with altered neurosteroid metabolism, mainly Niemann-Pick type C, multiple sclerosis and Alzheimer disease. Finally, we summarise the use of natural and synthetic neurosteroids as current and emerging therapeutics alongside their potential use as disease biomarkers.


2006 ◽  
Vol 37 (S 1) ◽  
Author(s):  
S Tay ◽  
X He ◽  
AM Jenner ◽  
BS Wong ◽  
WY Ong

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