Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency DOI Creative Commons

Vanitha Nithianadam,

Souvarish Sarkar, Mel Β. Feany

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 8, 2024

Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number genes, including electron transport components, in large forward genetic screen for mutations causing age-related neurodegeneration context proteostasis dysfunction. created model complex I deficiency Drosophila retina to probe role protein degradation abnormalities encephalomyopathies. Using our model, we found that regulates both ubiquitin/proteasome autophagy/lysosome arms machinery. further performed an vivo kinome uncover new potentially druggable mechanisms contributing related failure. Reduction RIOK kinases innate immune signaling kinase pelle prevented animals. Genetically targeting oxidative stress, but not RIOK1 or knockdown, normalized markers. Our findings outline distinct pathways controlling introduce experimentally facile which study these debilitating currently treatment-refractory disorders.

Language: Английский

Melatonin and retinal cell damage: molecular and biological functions DOI
Jingwen Sun, Yan Liu,

Zhangming Chen

et al.

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 9, 2024

Language: Английский

Citations

1

RTA408 alleviates retinal ganglion cells damage in mouse glaucoma by inhibiting excessive autophagy DOI Creative Commons

Hongmei Qian,

Wei Chen,

Guomei Yuan

et al.

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(11), P. e0313446 - e0313446

Published: Nov. 11, 2024

Glaucoma, characterized by a high incidence and significant ocular harm, has been elucidated through various mechanisms. Excessive autophagy leading to the loss of retinal ganglion cells (RGCs) is suggested as one potential cause for visual impairment in glaucoma.

Language: Английский

Citations

1

Loss of paired immunoglobin-like type 2 receptor B gene associated with age-related macular degeneration impairs photoreceptor function in mouse retina DOI Creative Commons
Partha Narayan Dey, Nivedita Singh, Lina Zelinger

et al.

Human Molecular Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 12, 2024

Genome-wide association studies have uncovered mostly non-coding variants at over 60 genetic loci linked to susceptibility for age-related macular degeneration (AMD). To ascertain the causal gene PILRB/PILRA locus, we used a CRISPR strategy produce germline deletions in mouse paired immunoglobin-like type 2 receptor (Pilr) genes that encode highly related activating (PILRB) and inhibitory (PILRA) receptors. We show combined loss of Pilrb1 Pilrb2, but not Pilra, leads an early relatively stationary defect as electroretinography (ERG) amplitudes Pilrb1/2-/- mice exhibit marked reduction postnatal day 15 do additional significant decrease 3 12-months. No alterations are evident Müller glia, microglia, bipolar, amacrine horizontal cells based on immunohistochemistry using cell-type specific markers. PILRB immunostaining is specifically detected proximal part photoreceptor outer segment. Reduced expression select calcium-regulated phototransduction synapse-associated proteins, including GCAP1 2, PDE6b, AIPL1, PSD95, CTBP1 indicates dysregulation calcium homeostasis possible mechanism retinal phenotype mice. Our suggest novel function photoreceptors PILRB, PILRA, with AMD pathogenesis.

Language: Английский

Citations

1

Sedentary Behavior Impacts on the Epigenome and Transcriptome: Lessons from Muscle Inactivation in Drosophila Larvae DOI Creative Commons
Avivit Brener, Dana Lorber,

Adriana Reuveny

et al.

Cells, Journal Year: 2023, Volume and Issue: 12(19), P. 2333 - 2333

Published: Sept. 22, 2023

The biological mechanisms linking sedentary lifestyles and metabolic derangements are incompletely understood. In this study, temporal muscle inactivation in Drosophila larvae carrying a temperature-sensitive mutation the shibire (shi1) gene was induced to mimic behavior during early life study its transcriptional outcome. Our findings indicated significant change epigenetic profile, as well genomic of RNA Pol II binding inactive muscles relative control, within relatively short time period. Whole-genome analysis RNA-Pol DNA by muscle-specific targeted DamID (TaDa) protocol revealed that inactivity altered 121 out 2010 genes (6%), with three-fold enrichment coding for lncRNAs. suppressed protein-coding included associated longevity, repair, function, ubiquitin-dependent proteostasis. Moreover, inducing exerted multi-level impact upon chromatin modifications, triggering an balance active versus marks. downregulated essential structure carbohydrate metabolism, others. Given multiple analogous many human genes, extrapolating our humans may hold promise establishing molecular link between diseases.

Language: Английский

Citations

1

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency DOI Creative Commons

Vanitha Nithianadam,

Souvarish Sarkar, Mel Β. Feany

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 8, 2024

Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number genes, including electron transport components, in large forward genetic screen for mutations causing age-related neurodegeneration context proteostasis dysfunction. created model complex I deficiency Drosophila retina to probe role protein degradation abnormalities encephalomyopathies. Using our model, we found that regulates both ubiquitin/proteasome autophagy/lysosome arms machinery. further performed an vivo kinome uncover new potentially druggable mechanisms contributing related failure. Reduction RIOK kinases innate immune signaling kinase pelle prevented animals. Genetically targeting oxidative stress, but not RIOK1 or knockdown, normalized markers. Our findings outline distinct pathways controlling introduce experimentally facile which study these debilitating currently treatment-refractory disorders.

Language: Английский

Citations

0