SPELL - Nematode

Citation	Okur MN, Fang EF, Fivenson EM, Tiwari V, Croteau DL, Bohr VA. Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺ signaling. Aging Cell, 2020.
PubMed ID	33166073
Short Description	Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺ signaling. GEO Record: GSE144556 GSE144558 Platform: GPL10094 Download gene-centric, log2 transformed data: WBPaper00064098.ce.mr.csv
# of Conditions	32
Full Description	Cockayne syndrome (CS) is a rare premature aging disease, most commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and have an average life expectancy of 12years. The CS proteins are involved in transcription and DNA repair, with the latter including transcription-coupled nucleotide excision repair (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, which likely contributes to the severe premature aging phenotype of this disease. While damaged mitochondria and impaired mitophagy were characterized in mice with CSB deficiency, such changes in the CS nematode model and CS patients are not fully known. Our cross-species transcriptomic analysis in CS postmortem brain tissue, CS mouse, and nematode models shows that mitochondrial dysfunction is indeed a common feature in CS. Restoration of mitochondrial dysfunction through NAD⁺ supplementation significantly improved lifespan and healthspan in the CS nematodes, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. In cerebellar samples from CS patients, we found molecular signatures of dysfunctional mitochondrial dynamics and impaired mitophagy/autophagy. In primary cells depleted for CSA or CSB, this dysfunction can be corrected with supplementation of NAD⁺ precursors. Our study provides support for the interconnection between major causative aging theories, DNA damage accumulation, mitochondrial dysfunction, and compromised mitophagy/autophagy. Together, these three agents contribute to an accelerated aging program that can be averted by cellular NAD⁺ restoration. Experimental Details: WBPaper00064098:N2_control_rep1 WBPaper00064098:N2_control_rep2 WBPaper00064098:N2_control_rep3 WBPaper00064098:N2_control_rep4 WBPaper00064098:N2_NAD+Precursor_rep1 WBPaper00064098:N2_NAD+Precursor_rep2 WBPaper00064098:N2_NAD+Precursor_rep3 WBPaper00064098:N2_NAD+Precursor_rep4 WBPaper00064098:csa-1(tm4539)_control_rep1 WBPaper00064098:csa-1(tm4539)_control_rep2 WBPaper00064098:csa-1(tm4539)_control_rep3 WBPaper00064098:csa-1(tm4539)_control_rep4 WBPaper00064098:csa-1(tm4539)_NAD+Precursor_rep1 WBPaper00064098:csa-1(tm4539)_NAD+Precursor_rep2 WBPaper00064098:csa-1(tm4539)_NAD+Precursor_rep3 WBPaper00064098:csa-1(tm4539)_NAD+Precursor_rep4 WBPaper00064098:csb-1(ok2335)_control_rep1 WBPaper00064098:csb-1(ok2335)_control_rep2 WBPaper00064098:csb-1(ok2335)_control_rep3 WBPaper00064098:csb-1(ok2335)_control_rep4 WBPaper00064098:csb-1(ok2335)_NAD+Precursor_rep1 WBPaper00064098:csb-1(ok2335)_NAD+Precursor_rep2 WBPaper00064098:csb-1(ok2335)_NAD+Precursor_rep3 WBPaper00064098:csb-1(ok2335)_NAD+Precursor_rep4 WBPaper00064098:csa-1(tm4539);csb-1(ok2335)_control_rep1 WBPaper00064098:csa-1(tm4539);csb-1(ok2335)_control_rep2 WBPaper00064098:csa-1(tm4539);csb-1(ok2335)_control_rep3 WBPaper00064098:csa-1(tm4539);csb-1(ok2335)_control_rep4 WBPaper00064098:csa-1(tm4539);csb-1(ok2335)_NAD+Precursor_rep1 WBPaper00064098:csa-1(tm4539);csb-1(ok2335)_NAD+Precursor_rep2 WBPaper00064098:csa-1(tm4539);csb-1(ok2335)_NAD+Precursor_rep3 WBPaper00064098:csa-1(tm4539);csb-1(ok2335)_NAD+Precursor_rep4.
Tags	Method: microarray, Species: Caenorhabditis elegans, Topic: response to chemical, Topic: WT vs. mutant