Niemann–Pick Disease

You are currently viewing Niemann–Pick Disease

Niemann–Pick Disease

Sphingomyelin-induced inhibition of the plasma membrane calcium ATPase causes neurodegeneration in type A Niemann–Pick disease.

An uncommon lysosomal storage condition called Niemann-Pick disease type A (NPA) causes significant neurological changes and is fatal in children. Acid sphingomyelinase (ASM) gene loss-of-function mutations lead to NPA and a buildup of sphingomyelin (SM) in neurons’ plasma membranes and lysosomes. Researchers have looked at how high SM levels affect brain damage in NPA using ASM knockout (ASMko) mice as a disease model. In both the neurons from these mice and a patient with NPA, and discovered elevated levels of oxidative stress. The intracellular calcium level rises as a result of decreased PMCA activity. SM causes PMCA activity to diminish, which results in oxidative stress. By restoring PMCA activity and calcium homeostasis in ASMko-cultured neurons, the histone deacetylase inhibitor SAHA lowers the elevated levels of oxidative stress. When PMCA activity is pharmacologically or genetically suppressed in vitro, no recovery takes place. In ASMko mice, oral treatment of SAHA reduces oxidative stress and neurodegeneration and enhances behavior. These findings show that plasma membrane SM plays a significant role in the control of neuronal calcium. As a result, researchers pinpoint PMCA-triggered calcium homeostasis modifications as an early mediator of NPA pathogenesis. These discoveries may inspire fresh ideas for pharmacological therapy of a condition for which there are no available therapeutic remedies.

Niemann–Pick Disease

Although the precise underlying processes in each lysosomal storage disorder are likely to vary, this article hypothesizes that oxidative stress and a lack of calcium homeostasis are similar aspects that underpin the pathophysiology of several lysosomal storage disorders, including NPA. The functional ramifications that result from NPA disease and other lysosomal storage disorders can be understood by understanding the processes that encourage oxidative stress and impaired calcium homeostasis.In this article, researchers define neuronal oxidative stress as a pathogenic characteristic of NPA. We find buildup of SM, altered PMCA activity, and disturbed calcium homeostasis using the ASMko mouse model for NPA. They show that abnormally high intracellular calcium levels in these cells are caused by excessive SM accumulation at the neuronal plasma membrane, which enhances oxidative stress and neuronal death. The elevated calcium levels are caused by changes in the plasma membrane calcium pump PMCA’s function. These findings show that in ASM-deficient neurons, altered calcium imbalance is a key modification that occurs prior to oxidative stress. (MT, 2013; ) (Brady RO, 1996)Researchers find a non-invasive pharmaceutical method that can successfully treat symptoms of this condition both in vitro and in vivo, and which may avoid the brain abnormalities that come along with ASM deficiency. Neuronal membranes, where SM is abundant, serve a variety of purposes. Indeed, maintaining axonal polarity and synaptic plasticity depends on proper SM levels.

Niemann–Pick Disease

SM may have an immediate impact on PMCA folding or may have an indirect impact by affecting how it interacts with binding proteins, for as through changing raft compartmentalization. As seen in ASMko neurons, SM may also change actin polymerization, which could change PMCA activity. Due to this calcium pump’s high sensitivity to ROS-induced cross-linking, oxidative stress brought on by PMCA deficiency may also activate a negative feedback loop that amplifies the effects of this calcium pump. Regardless of the precise mechanisms behind PMCA deficiency, changes in intracellular calcium concentrations probably disrupt critical physiological processes in ASM-deficient neurons. Signal transduction pathways and membrane healing procedures may be impacted by these mechanisms. In reality, ASM-deficient cells do have poor plasma membrane repair. SM is converted to ceramide during ASM translocation to the plasma membrane by calcium-dependent lysosomal exocytosis, which then initiates endocytosis and wound healing. A foundation for the development of both generic and disease-specific treatment approaches will be established by a more thorough knowledge of the molecular pathways that alter calcium homeostasis and their functional repercussions in each LSD. In cellular models of NPC, therapy with deacetylase inhibitors has been effective, despite the fact that this treatment focused on lengthening the half-life of the cholesterol transport protein Npc1, which was altered in NPC but did not specifically alter the calcium imbalance. Our results show that SAHA therapy in ASMko mice can increase PMCA levels and reduce oxidative stress in a PMCA-dependent way, even if it may have other effects than PMCA activation. Contextual fear conditioning tests show that chronic treatment with SAHA can improve memory formation in wt mice. Researchers utilized a different behavioral experiment, nevertheless, and it failed to show any effects of SAHA therapy on the wt mice’s cognitive function. This gap can be explained by the degree of HDAC inhibition attained in our experimental paradigm. According to pharmacokinetic studies, HDAC2, a key player in fear memory, has the greatest IC for SAHA when compared to other HDACs. However, the fact that SAHA enhances memory in ASMko animals with disturbed neuronal calcium homeostasis but not in wt mice shows that the cognitive advantages of SAHA are instead brought about by the correction of the endogenous calcium imbalance rather than by increased synaptic activity.

Hi there 👋
It’s nice to meet you.

Sign up to receive awesome content in your inbox.

We don’t spam! Read our privacy policy for more info.

This Post Has 3 Comments

  1. vorbelutr ioperbir

    Great write-up, I am regular visitor of one’s web site, maintain up the nice operate, and It’s going to be a regular visitor for a lengthy time.

  2. binance Registrace

    Can you be more specific about the content of your article? After reading it, I still have some doubts. Hope you can help me.

Leave a Reply