A C. elegans model for neurodegeneration in Cockayne syndrome

Abstract

Cockayne syndrome (CS) is a congenital syndrome characterized by growth and mental retardation, and premature ageing. The complexity of CS and mammalian models warrants simpler metazoan models that display CS-like phenotypes that could be studied in the context of a live organism. Here, we provide a characterization of neuronal and mitochondrial aberrations caused by a mutation in the csb-1 gene in Caenorhabditis elegans. We report a progressive neurodegeneration in adult animals that is enhanced upon UV-induced DNA damage. The csb-1 mutants show dysfunctional hyperfused mitochondria that degrade upon DNA damage, resulting in diminished respiratory activity. Our data support the role of endogenous DNA damage as a driving factor of CS-related neuropathology and underline the role of mitochondrial dysfunction in the disease.

Whole Exome Sequencing Identifies a Novel Homozygous Missense Mutation in the CSB Protein-Encoding ERCC6 Gene in a Taiwanese Boy with Cockayne Syndrome

“…These above studies collectively suggest that the pathogenicity of the missense mutation, Leu536Trp, as well as the Asp532Gly mutation, which are both found in ATPase motif I, may cause the loss of the ability of CSB to repair damaged DNA, leading to neurodegeneration and mitochondrial dysfunction in CS patients [30]. This idea is further supported by a Caenorhabditis elegans model that demonstrates the role of endogenous DNA damage as a driving factor of CS-related neuropathology and underlines the neuronal and mitochondrial aberrations observed in the disease [31].…”

The Mitochondrial Response to DNA Damage

“…Replication errors are likely the main sources of de novo mtDNA mutations. Accumulation of certain types of mtDNA mutations may trigger cell death and lead to age-related diseases, such as PD, Cockayne syndrome (CS), and Werner syndrome (WS) ( Palikaras et al, 2015 ; Fang et al, 2019 ; Lopes et al, 2020 ).…”

Principles of the Molecular and Cellular Mechanisms of Aging

“…Age-dependent mitochondrial dysfunction stems from many sources, including accumulation of mtDNA mutations, dysfunction of mitochondrial proteins, structural alterations in mitochondrial membranes, imbalance between fission and fusion events, and defective clearance of damaged mitochondria by mitophagy (Ló pez-Otín et al, 2013). Mitochondrial dysfunction was suggested to be a consequence of nuclear DNA repair deficiencies (Chang et al, 2015;Hussain et al, 2021) and might account for some of the degenerative pathologies such as neurodegeneration, for example, in CS (Fang et al, 2016;Lopes et al, 2020).…”