Systematic spatiotemporal mapping reveals divergent cell death pathways in three mouse models of hereditary retinal degeneration

Programmed cell death (PCD) is a highly regulated process that results in the orderly destruction of a cell. Many different forms of PCD may be distinguished, including apoptosis, PARthanatos, and cGMP-dependent cell death. Misregulation of PCD mechanisms may be the underlying cause of neurodegenerative diseases of the retina, including hereditary retinal degeneration (RD). RD relates to a group of diseases that affect photoreceptors and that are triggered by gene mutations that are often well known nowadays. Nevertheless, the cellular mechanisms of PCD triggered by disease-causing mutations are still poorly understood, and RD is mostly still untreatable. While investigations into the neurodegenerative mechanisms of RD have focused on apoptosis in the past two decades, recent evidence suggests a predominance of non-apoptotic processes as causative mechanisms. Research into these mechanisms carries the hope that the knowledge created can eventually be used to design targeted treatments to prevent photoreceptor loss. Hence, in this review, we summarize studies on PCD in RD, including on apoptosis, PARthanatos, and cGMP-dependent cell death. Then, we focus on a possible interplay between these mechanisms, covering cGMP-signaling targets, overactivation of poly(ADP-ribose)polymerase (PARP), energy depletion, Ca2+-permeable channels, and Ca2+-dependent proteases. Finally, an outlook is given into how specific features of cGMP-signaling and PARthanatos may be targeted by therapeutic interventions.

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Cell Death Pathways in Mutant Rhodopsin Rat Models Identifies Genotype-Specific Targets Controlling Retinal Degeneration

Molecular Neurobiology ◽

10.1007/s12035-018-1192-8 ◽

2018 ◽

Vol 56 (3) ◽

pp. 1637-1652 ◽

Cited By ~ 6

Author(s):

Ishaq A. Viringipurampeer ◽

Cheryl Y. Gregory-Evans ◽

Andrew L. Metcalfe ◽

Emran Bashar ◽

Orson L. Moritz ◽

...

Keyword(s):

Cell Death ◽

Retinal Degeneration ◽

Rat Models ◽

Cell Death Pathways

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Systematic spatio-temporal mapping reveals divergent cell death pathways in three mouse models of hereditary retinal degeneration

10.1101/554733 ◽

2019 ◽

Author(s):

M.J. Power ◽

L.E. Rogerson ◽

T. Schubert ◽

P. Berens ◽

T. Euler ◽

...

Keyword(s):

Cell Death ◽

Gaussian Process ◽

Retinal Degeneration ◽

Caspase 3 ◽

Photoreceptor Cell ◽

Process Models ◽

Calpain Activity ◽

Gaussian Process Models ◽

Hereditary Retinal Degeneration ◽

Spatio Temporal

AbstractCalcium (Ca2+) dysregulation has been linked to neuronal cell death, including in hereditary retinal degeneration. Ca2+ dysregulation is thought to cause rod and cone photoreceptor cell death. Spatial and temporal heterogeneities in retinal disease models have hampered validation of this hypothesis.We examined the role of Ca2+ in photoreceptor degeneration, assessing the activation pattern of Ca2+-dependent calpain proteases, generating spatio-temporal maps of the entire retina in the cpfl1 mouse model for primary cone degeneration, and in the rd1 and rd10 models for primary rod degeneration. We used Gaussian process models to distinguish the temporal sequences of degenerative molecular processes from other variability sources.In the rd1 and rd10 models, spatio-temporal pattern of increased calpain activity matched the progression of primary rod degeneration. High calpain activity coincided with activation of the calpain-2 isoform but not with calpain-1, suggesting differential roles for both calpain isoforms. Primary rod loss was linked to upregulation of apoptosis-inducing factor (AIF), although only a minute fraction of cells showed activity of the apoptotic marker caspase-3. After primary rod degeneration concluded, caspase-3 activation appeared in cones, suggesting apoptosis as the dominant mechanism for secondary cone loss. Gaussian process models highlighted calpain activity as a key event during primary rod photoreceptor cell death.Our data suggests a causal link between Ca2+ dysregulation and primary, non-apoptotic degeneration of photoreceptors and a role for apoptosis in secondary degeneration of cones, highlighting the importance of the spatial and temporal location of key molecular events, which may guide the evaluation of new therapies.

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Development and Challenges of Nanotherapeutic Formulations for Targeting Mitochondrial Cell Death Pathways in Lung and Brain Degenerative Diseases

Critical Reviews in Biomedical Engineering ◽

10.1615/critrevbiomedeng.2020034546 ◽

2020 ◽

Vol 48 (3) ◽

pp. 137-152

Author(s):

Marko Manevski ◽

Dinesh Devadoss ◽

Ruben Castro ◽

Lauren Delatorre ◽

Adriana Yndart ◽

...

Keyword(s):

Cell Death ◽

Degenerative Diseases ◽

Cell Death Pathways

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Proteomic Analysis of Exosomes Released from Heatstressed Hepatocytes Reveals Promotion of Programmed Cell Death Pathways

SSRN Electronic Journal ◽

10.2139/ssrn.3279179 ◽

2018 ◽

Author(s):

Yue Li ◽

Xintao Zhu ◽

Guozhen Wang ◽

Huasheng Tong ◽

Xuguang Ling ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Proteomic Analysis ◽

Cell Death Pathways

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Treatment with ascorbic acid normalizes the aerobic capacity, antioxidant defence, and cell death pathways on thermally stressed Mytilus galloprovincialis

Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology ◽

10.1016/j.cbpb.2021.110611 ◽

2021 ◽

pp. 110611

Author(s):

Konstantinos Feidantsis ◽

Ioannis Georgoulis ◽

Ioannis A. Giantsis ◽

Basile Michaelidis

Keyword(s):

Cell Death ◽

Ascorbic Acid ◽

Aerobic Capacity ◽

Mytilus Galloprovincialis ◽

Antioxidant Defence ◽

Cell Death Pathways ◽

Thermally Stressed

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Immunogenomic Gene Signature of Cell-Death Associated Genes with Prognostic Implications in Lung Cancer

Cancers ◽

10.3390/cancers13010155 ◽

2021 ◽

Vol 13 (1) ◽

pp. 155

Author(s):

Pankaj Ahluwalia ◽

Meenakshi Ahluwalia ◽

Ashis K. Mondal ◽

Nikhil Sahajpal ◽

Vamsi Kota ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

Cell Death ◽

T Cell ◽

High Risk ◽

Lung Adenocarcinoma ◽

Risk Group ◽

High Risk Group ◽

Free Survival ◽

Cell Death Pathways

Lung cancer is one of the leading causes of death worldwide. Cell death pathways such as autophagy, apoptosis, and necrosis can provide useful clinical and immunological insights that can assist in the design of personalized therapeutics. In this study, variations in the expression of genes involved in cell death pathways and resulting infiltration of immune cells were explored in lung adenocarcinoma (The Cancer Genome Atlas: TCGA, lung adenocarcinoma (LUAD), 510 patients). Firstly, genes involved in autophagy (n = 34 genes), apoptosis (n = 66 genes), and necrosis (n = 32 genes) were analyzed to assess the prognostic significance in lung cancer. The significant genes were used to develop the cell death index (CDI) of 21 genes which clustered patients based on high risk (high CDI) and low risk (low CDI). The survival analysis using the Kaplan–Meier curve differentiated patients based on overall survival (40.4 months vs. 76.2 months), progression-free survival (26.2 months vs. 48.6 months), and disease-free survival (62.2 months vs. 158.2 months) (Log-rank test, p < 0.01). Cox proportional hazard model significantly associated patients in high CDI group with a higher risk of mortality (Hazard Ratio: H.R 1.75, 95% CI: 1.28–2.45, p < 0.001). Differential gene expression analysis using principal component analysis (PCA) identified genes with the highest fold change forming distinct clusters. To analyze the immune parameters in two risk groups, cytokines expression (n = 265 genes) analysis revealed the highest association of IL-15RA and IL 15 (> 1.5-fold, p < 0.01) with the high-risk group. The microenvironment cell-population (MCP)-counter algorithm identified the higher infiltration of CD8+ T cells, macrophages, and lower infiltration of neutrophils with the high-risk group. Interestingly, this group also showed a higher expression of immune checkpoint molecules CD-274 (PD-L1), CTLA-4, and T cell exhaustion genes (HAVCR2, TIGIT, LAG3, PDCD1, CXCL13, and LYN) (p < 0.01). Furthermore, functional enrichment analysis identified significant perturbations in immune pathways in the higher risk group. This study highlights the presence of an immunocompromised microenvironment indicated by the higher infiltration of cytotoxic T cells along with the presence of checkpoint molecules and T cell exhaustion genes. These patients at higher risk might be more suitable to benefit from PD-L1 blockade or other checkpoint blockade immunotherapies.

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