Reduction of glutamate neurotoxicity: A novel therapeutic approach for Niemann-Pick disease, type C1

Cougnoux, Antony; Yerger, Julia; Fellmeth, Mason; Serra-Vinardell, Jenny; Navid, Fatemeh; Wassif, Christopher A.; Cawley, Niamh X.; Porter, Forbes D.

doi:10.1016/j.ymgme.2021.11.008

Cited by 8 publications

(7 citation statements)

References 47 publications

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“…This makes the need for further determining mechanisms and identifying new targets more imperative [ 163 ]. Genetic diseases such as the autosomal recessive Niemann–Pick disease, with known biochemical defects of myelin sheath production and maintenance, provide insights into degenerative processes and are suggestive of glutamate involvement [ 164 ]. Excitotoxicity by glutamatergic overstimulation is becoming recognised as a central feature of many neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease, and Huntington’s disease [ 165 , 166 , 167 ].…”

Section: Neurodegenerative Conditions and Glutamatementioning

confidence: 99%

Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases

et al. 2022

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The monoamine model of depression has long formed the basis of drug development but fails to explain treatment resistance or associations with stress or inflammation. Recent animal research, clinical trials of ketamine (a glutamate receptor antagonist), neuroimaging research, and microbiome studies provide increasing evidence of glutamatergic dysfunction in depression and other disorders. Glutamatergic involvement across diverse neuropathologies including psychoses, neurodevelopmental, neurodegenerative conditions, and brain injury forms the rationale for this review. Glutamate is the brain’s principal excitatory neurotransmitter (NT), a metabolic and synthesis substrate, and an immune mediator. These overlapping roles and multiple glutamate NT receptor types complicate research into glutamate neurotransmission. The glutamate microcircuit comprises excitatory glutamatergic neurons, astrocytes controlling synaptic space levels, through glutamate reuptake, and inhibitory GABA interneurons. Astroglia generate and respond to inflammatory mediators. Glutamatergic microcircuits also act at the brain/body interface via the microbiome, kynurenine pathway, and hypothalamus–pituitary–adrenal axis. Disruption of excitatory/inhibitory homeostasis causing neuro-excitotoxicity, with neuronal impairment, causes depression and cognition symptoms via limbic and prefrontal regions, respectively. Persistent dysfunction reduces neuronal plasticity and growth causing neuronal death and tissue atrophy in neurodegenerative diseases. A conceptual overview of brain glutamatergic activity and peripheral interfacing is presented, including the common mechanisms that diverse diseases share when glutamate homeostasis is disrupted.

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Section: Neurodegenerative Conditions and Glutamatementioning

confidence: 99%

Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases

et al. 2022

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“…However, given the crucial roles of CaMKII at the synapse and specifically in the hippocampus, , the activity and signaling pathway involving this protein in the context of NPC should be further explored. Interestingly, glutamate toxicity has been explored in NPC1 disease further supporting the need to extend studies of LTP and receptor function in NPC …”

Section: Resultsmentioning

confidence: 99%

Comparative Hippocampal Proteome and Phosphoproteome in a Niemann–Pick, Type C1 Mouse Model Reveal Insights into Disease Mechanisms

Nguyen,

Mohanty,

Yan

et al. 2023

J. Proteome Res.

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Niemann−Pick disease, type C (NPC) is a neurodegenerative, lysosomal storage disorder in individuals carrying two mutated copies of either the NPC1 or NPC2 gene. Consequently, impaired cholesterol recycling and an array of downstream events occur. Interestingly, in NPC, the hippocampus displays lysosomal lipid storage but does not succumb to progressive neurodegeneration as significantly as other brain regions. Since defining the neurodegeneration mechanisms in this disease is still an active area of research, we use mass spectrometry to analyze the overall proteome and phosphorylation pattern changes in the hippocampal region of a murine model of NPC. Using 3 week old mice representing an early disease time point, we observed changes in the expression of 47 proteins, many of which are consistent with the previous literature. New to this study, changes in members of the SNARE complex, including STX7, VTI1B, and VAMP7, were identified. Furthermore, we identified that phosphorylation of T286 on CaMKIIα and S1303 on NR2B increased in mutant animals, even at the late stage of the disease. These phosphosites are crucial to learning and memory and can trigger neuronal death by altering protein−protein interactions.

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“…These data suggest that miglustat treatment in individuals with NPC1 reduces the neuroinflammation at some level. Alternatively, noting that individuals with NPC1 have seizures [60], which is due to neuronal hyperexcitability, upregulation of NPY in individuals with NPC1 could potentially be a complementary regulatory mechanism to decrease neuronal hyperexcitability [61]. It is reasonable to consider the role of NPY in the nitric oxide (NO) pathway which has been noted to be altered in the current study (Figure 3).…”

Section: Discussionmentioning

confidence: 97%

A differential proteomics study of cerebrospinal fluid from individuals with Niemann‐Pick disease, Type C1

Pergande

Crutchfield

et al. 2023

Proteomics

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Niemann-Pick, type C1 (NPC1) is a fatal, neurodegenerative disease, which belongs to the family of lysosomal diseases. In NPC1, endo/lysosomal accumulation of unesterified cholesterol and sphingolipids arise from improper intracellular trafficking resulting in multi-organ dysfunction. With the proximity between the brain and cerebrospinal fluid (CSF), performing differential proteomics provides a means to shed light to changes occurring in the brain. In this study, CSF samples obtained from NPC1 individuals and unaffected controls were used for protein biomarker identification. A subset of these individuals with NPC1 are being treated with miglustat, a glycosphingolipid synthesis inhibitor. Of the 300 identified proteins, 71 proteins were altered in individuals with NPC1 compared to controls including cathepsin D, and members of the complement family. Included are a report of 10 potential markers for monitoring therapeutic treatment. We observed that pro-neuropeptide Y (NPY) was significantly increased in NPC1 individuals relative to healthy controls; however, individuals treated with miglustat displayed levels comparable to healthy controls. In further investigation, NPY levels in a NPC1 mouse model corroborated our findings. We posit that NPY could be a potential therapeutic target for NPC1 due to its multiple roles in the central nervous system such as attenuating neuroinflammation and reducing excitotoxicity.

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Reduction of glutamate neurotoxicity: A novel therapeutic approach for Niemann-Pick disease, type C1

Cited by 8 publications

References 47 publications

Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases

Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases

Comparative Hippocampal Proteome and Phosphoproteome in a Niemann–Pick, Type C1 Mouse Model Reveal Insights into Disease Mechanisms

A differential proteomics study of cerebrospinal fluid from individuals with Niemann‐Pick disease, Type C1

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