Patient-Specific iPSCs-Based Models of Neurodegenerative Diseases: Focus on Aberrant Calcium Signaling
Abstract
:1. Introduction
2. Problems and Prospects of iPSCs-Based Models of Neurodegenerative Diseases
3. Obtaining the iPSCs-Based Models of Neurodegenerative Diseases
4. Neurodegeneration and Calcium Signaling
5. Alzheimer’s Disease
6. Parkinson’s Disease
7. Huntington’s Disease
8. Spinocerebellar Ataxias
9. Amyotrophic Lateral Sclerosis
10. Other Neurological Diseases
10.1. Autism Spectrum Disorders
10.2. Leigh’s Syndrome
11. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Alzheimer’s Disease | |||
---|---|---|---|
The most vulnerable areas of the brain | iPSCs-based models | ||
Patient-specific models | |||
Neurons | [37,46,48,97,99,100,101,102,103,104] | ||
Cortical neurons | [105,106] | ||
Cholinergic neurons | [107] | ||
Astrocytes | [105,108] | ||
Endothelial cells | [72,109] | ||
Microglia | [67,69] | ||
Isogenic models | |||
Neurons | [37,38,39,98] | ||
Mutant genes | Cell type | Disturbance associated with calcium signaling | |
PSEN1 | Neurons | Increased ROS production, impaired energy status and mitochondrial potential, impaired autophagy, ER stress and increased calcium release from the ER | [104] |
Astrocytes | Disturbed calcium release from the ER, increased ROS production | [108] | |
PSEN2 | Neurons | Increased amplitude of spontaneous calcium oscillations and their desynchronization, hyperactivation of neurons | [99] |
APP | Astrocytes | ER stress, increased ROS production | [105] |
Sporadic forms | Neurons | Mitochondrial dysfunction, increased ROS production, increased levels of oxidative phosphorylation chain complexes | [103] |
Parkinson’s Disease | |||
---|---|---|---|
The most vulnerable areas of the brain | iPSCs-based models | ||
Patient-specific models | |||
NESC | [117] | ||
Dopaminergic neurons (DAn) | [51,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,138] | ||
Cortical neurons | [137] | ||
Astrocytes | [66] | ||
Microglia | [68] | ||
Isogenic models | |||
DAn | [41,45] | ||
Cortical neurons | [43] | ||
Mutant genes | Cell type | Disturbance associated with calcium signaling | |
LRRK2 | NESC | Mitochondrial dysfunction, impaired mitophagy | [117] |
DAn | Enhanced expression of genes involved in calcium signaling, as well as an increase in calcium influx, mitochondrial dysfunction, mitochondrial DNA damage, oxidative stress, disrupted calcium dynamics in the ER | [120,121,124,125,127,131,132,136,138] | |
SNCA | Cortical neurons | Mitochondrial dysfunction, oxidative stress | [137] |
DAn | Mitochondrial dysfunction, ER stress, impaired calcium homeostasis and ATP production | [43,119,130,131,135,139] | |
PINK1 | DAn | Mitochondrial dysfunction, oxidative stress, slowed utilization of damaged mitochondria | [133] |
PARK2 | DAn | Mitochondrial dysfunction, oxidative stress, dysfunction of voltage-gated T-type calcium channels | [41,51,134,140] |
DJ-1 | DAn | Oxidative stress | [129] |
Huntington’s Disease | |||
---|---|---|---|
The most vulnerable areas of the brain | iPSCs-based models | ||
Patient-specific models | |||
iPSCs | [50] | ||
NPC | [52,152,153,161] | ||
Cortical neurons | [154] | ||
GABAergic neurons | [8,61,155,156,157,158] | ||
Astrocytes | [159,160] | ||
Endothelial cells | [71] | ||
Mixed cultures | [73] | ||
Isogenic models | |||
NPC | [44] | ||
GABAergic neurons | [36] | ||
Mutant genes | Cell type | Disturbance associated with calcium signaling | |
HTT | iPSCs | Impaired expression of the genes responsible for cell death | [50] |
Mixed cultures | Impaired expression of genes responsible for calcium signaling | [73] | |
GABAergic neurons | Increased store-operated calcium entry and calcium currents through voltage-gated calcium channels in low-repet and juvenile models of Huntington’s disease | [8,61,157] | |
GABAergic neurons | Increased mitochondrial density | [156] | |
GABAergic neurons | Dysfunction of lysosomes and autophagy | [8,155] | |
NPC | Mitochondrial dysfunction, bioenergetic defects | [44,161] |
Spinocerebellar Ataxias | |||
---|---|---|---|
The most vulnerable areas of the brain | iPSCs-based models | ||
Patient-specific models | |||
iPSCs | [193] | ||
NPC | [176,177] | ||
Neurons | [58,59,60,174,175,180,182,183,184,185,186,187,188,190,192] | ||
Cortical neurons | [179,181,194] | ||
Motoneurons (MNs) | [195] | ||
GABAergic and glutamatergic neurons | [189] | ||
Purkinje cells | [167,170,171,172,173] | ||
Mixed cultures | [178] | ||
Isogenic models | |||
NPC | [191] | ||
Purkinje cells | [42] | ||
Mutant genes | Cell type | Disturbance associated with calcium signaling | |
ATXN1(SCA1) | GABAergic neurons | Decreased store-operated calcium entry, no changes in the functioning of voltage-gated calcium channels | Vigont et al., unpublished data |
ATXN2 & 3(SCA2 & 3) | Mixed cultures | Altered expression of glutamate receptor subunits and other participants in calcium signaling. Increased calcium concentration in the cytosol. Distorted mitochondrial microstructures and mitochondrial dysfunction | [178] |
ATXN3(SCA3) | Cortical neurons | Mitochondrial fragmentation and cristae alterations leading to decreased capacity of mitochondrial respiration, impaired mitochondrial degradation. Enhanced calpains-activated ataxin 3 cleavage and produce ataxin 3 fragments. | [58,179,181] |
CACNA1A (SCA6) | GABAergic& glutamatergic neurons | No differences in both CACNA1A expression and amplitudes of voltage-gated calcium currents | [189] |
ATXN7(SCA7) | NPC | Decreased mitochondrial network length. Mitochondrial dysfunction, reduced oxygen consumption rate and increased extracellular acidification rate | [191] |
TBP(SCA17) | GABAergic neurons | Increased store-operated calcium entry and voltage-gated calcium uptake | Vigont et al., unpublished data |
Amyotrophic Lateral Sclerosis | |||
---|---|---|---|
The most vulnerable areas of the brain | iPSCs-based models | ||
Patient-specific models | |||
Motoneurons (MNs) | [64,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219] | ||
Cortical neurons | [205] | ||
Astrocytes | [202,224,225] | ||
Oligodendrocyte | [226] | ||
Isogenic models | |||
Motoneurons (MNs) | [43] | ||
Mutant genes | Cell type | Disturbance associated with calcium signaling | |
C9orf72 | MNs | Transcriptional changes in levels of the mitochondrial transporter, increased expression of genes encoding glutamate receptors and VGCC. Increased glutamate excitotoxicity C9ORF72 iPSN cultures. Disrupted mitochondrial calcium buffering capacity, low calbindin levels | [204,217,218,219,221] |
TARDBP | MNs | Increased expression of genes encoding glutamate receptors. Elevated basal intracellular calcium levels. Increased conductance for calcium AMPA and NMDA receptors. Imbalance in mitochondrial calcium buffering capacity | [217,218,219] |
SOD1 | MNs | Transcriptional and functional changes: defects in mitochondrial transport, morphology and motility, increase in mitochondrial density, oxidative and ER-related stress. Reduced level of calcium-binding proteins. | [220,221] |
FUS | MNs | No morphological changes in the mitochondria, decreased mitochondrial motility | [223] |
Sporadic form | MNs | Deregulated expression of the genes associated with mitochondrial functioning | [209] |
Other Neurological Pathologies | |||
---|---|---|---|
The most vulnerable areas of the brain | iPSCs-based models | ||
Patient-specific models | |||
NPC (LS) | [237] | ||
Neurons (ASD) | [234,235,236] | ||
Cortical neurons (ASD) | [238] | ||
Mutant genes | Cell type | Disturbance associated with calcium signaling | |
Genes encoding VGCC subunits (ASD) | Neurons | Altered expression of genes responsible for calcium signaling. Dysfunction of voltage-gated channels. Increased nimodipine sensitive calcium influx after depolarization. | [234,235] |
mtDNA m.13513G (LS) | NPC | Mitochondrial dysfunction, decreased calcium buffering capacity | [237] |
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Grekhnev, D.A.; Kaznacheyeva, E.V.; Vigont, V.A. Patient-Specific iPSCs-Based Models of Neurodegenerative Diseases: Focus on Aberrant Calcium Signaling. Int. J. Mol. Sci. 2022, 23, 624. https://doi.org/10.3390/ijms23020624
Grekhnev DA, Kaznacheyeva EV, Vigont VA. Patient-Specific iPSCs-Based Models of Neurodegenerative Diseases: Focus on Aberrant Calcium Signaling. International Journal of Molecular Sciences. 2022; 23(2):624. https://doi.org/10.3390/ijms23020624
Chicago/Turabian StyleGrekhnev, Dmitriy A., Elena V. Kaznacheyeva, and Vladimir A. Vigont. 2022. "Patient-Specific iPSCs-Based Models of Neurodegenerative Diseases: Focus on Aberrant Calcium Signaling" International Journal of Molecular Sciences 23, no. 2: 624. https://doi.org/10.3390/ijms23020624