Disease-associated mutations in Niemann-Pick type C1 alter ER calcium signaling and neuronal plasticity

Tiscione, Scott A.; Vivas, Oscar; Ginsburg, Kenneth S.; Bers, Donald M.; Ory, Daniel S.; Santana, Luis Fernando; Dixon, Rose E.; Dickson, Eamonn J.

doi:10.1083/jcb.201903018

Cited by 35 publications

(58 citation statements)

References 65 publications

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“…Two studies in NPC1 neurons obtained controversial results: while Xu et al (2010) reported no differences in spine density [63], Tiscione et al (2019) observed that NPC1 deficiency results in a decrease in neuronal spine density [106]. Thus, based on the published data, it appears that alterations of synaptic spines do not follow the same trend among all neurological LSD.…”

Section: Defects In Synaptic Spinesmentioning

confidence: 99%

Neuropathophysiology of Lysosomal Storage Diseases: Synaptic Dysfunction as a Starting Point for Disease Progression

Pará

Bose

Pshezhetsky

2020

JCM

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About two thirds of the patients affected with lysosomal storage diseases (LSD) experience neurological manifestations, such as developmental delay, seizures, or psychiatric problems. In order to develop efficient therapies, it is crucial to understand the neuropathophysiology underlying these symptoms. How exactly lysosomal storage affects biogenesis and function of neurons is still under investigation however recent research highlights a substantial role played by synaptic defects, such as alterations in synaptic spines, synaptic proteins, postsynaptic densities, and synaptic vesicles that might lead to functional impairments in synaptic transmission and neurodegeneration, finally culminating in massive neuronal death and manifestation of cognitive symptoms. Unveiling how the synaptic components are affected in neurological LSD will thus enable a better understanding of the complexity of disease progression as well as identify crucial targets of therapeutic relevance and optimal time windows for targeted intervention.

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Section: Defects In Synaptic Spinesmentioning

confidence: 99%

Neuropathophysiology of Lysosomal Storage Diseases: Synaptic Dysfunction as a Starting Point for Disease Progression

Pará

Bose

Pshezhetsky

2020

JCM

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“…In the study by Tiscione et al (4), several key conclusions can be made. First, the loss of function of the NPC1 cholesterol transporter results in increased flux of Ca 2+ at the plasma membrane, yet decreased ER Ca 2+ levels and overall increased resting cytosolic Ca 2+ in NPC patient fibroblasts with different disease-causing mutations in the NPC1 gene as well as in NPC1 null cells and a pharmacologically induced NPC cell model.…”

mentioning

confidence: 98%

“…Going back to the cholesterol defect in NPC, the study explores the role of the classical cholesterol biosynthesis and regulation pathways, namely, the membrane-bound sterol regulatory element binding protein (SREBP) pathway. From their data, the authors conclude that activation of SREBP contributes to the Ca 2+ imbalance and signaling protein defects observed in NPC (4).…”

mentioning

confidence: 99%

“…Intracellular Ca 2+ levels are regulated by activation of a variety of ion channels in the plasma membrane and the ER, which stores a substantial amount of Ca 2+ (2, 3). In , altered Ca 2+ dynamics are shown in the fatal, lysosomal storage disease, Niemann-Pick type C (NPC; 4).…”

mentioning

confidence: 99%

“…Ultimately, one may argue that understanding the mechanisms of defects to the central nervous system in NPC are the most critical aspects for making progress in the development of new therapies. Appropriately, Tiscione et al (4) evaluate these observed deficits from their fibroblasts studies to cultured hippocampal neurons using the pharmacological NPC model and also in a point mutant mouse model of NPC. The authors find that neuronal Ca 2+ is also decreased at the ER, whereas an increase in cytoplasmic Ca 2+ is noted.…”

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confidence: 99%

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A calcium message for Niemann-Pick type C

Cologna

2019

Journal of Cell Biology

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Graphene Microelectrode Arrays, 4D Structured Illumination Microscopy, and a Machine Learning Spike Sorting Algorithm Permit the Analysis of Ultrastructural Neuronal Changes During Neuronal Signaling in a Model of Niemann–Pick Disease Type C

Lu,

Hui,

Brockhoff

et al. 2024

Advanced Science

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Simultaneously recording network activity and ultrastructural changes of the synapse is essential for advancing understanding of the basis of neuronal functions. However, the rapid millisecond‐scale fluctuations in neuronal activity and the subtle sub‐diffraction resolution changes of synaptic morphology pose significant challenges to this endeavor. Here, specially designed graphene microelectrode arrays (G‐MEAs) are used, which are compatible with high spatial resolution imaging across various scales as well as permit high temporal resolution electrophysiological recordings to address these challenges. Furthermore, alongside G‐MEAs, an easy‐to‐implement machine learning algorithm is developed to efficiently process the large datasets collected from MEA recordings. It is demonstrated that the combined use of G‐MEAs, machine learning (ML) spike analysis, and 4D structured illumination microscopy (SIM) enables monitoring the impact of disease progression on hippocampal neurons which are treated with an intracellular cholesterol transport inhibitor mimicking Niemann–Pick disease type C (NPC), and show that synaptic boutons, compared to untreated controls, significantly increase in size, leading to a loss in neuronal signaling capacity.

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Disease-associated mutations in Niemann-Pick type C1 alter ER calcium signaling and neuronal plasticity

Abstract: Tiscione et al. report a molecular mechanism that links lysosomal cholesterol export with the regulation of key intracellular Ca2+ signaling pathways to influence synaptic architecture in health and neurodegenerative NPC1 disease.

Cited by 35 publications

References 65 publications

Neuropathophysiology of Lysosomal Storage Diseases: Synaptic Dysfunction as a Starting Point for Disease Progression

Neuropathophysiology of Lysosomal Storage Diseases: Synaptic Dysfunction as a Starting Point for Disease Progression

A calcium message for Niemann-Pick type C

Graphene Microelectrode Arrays, 4D Structured Illumination Microscopy, and a Machine Learning Spike Sorting Algorithm Permit the Analysis of Ultrastructural Neuronal Changes During Neuronal Signaling in a Model of Niemann–Pick Disease Type C

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