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.
Highlights
Cockayne syndrome (CS) is an autosomal recessive genetic disorder with an occurrence of 2.5 cases per million births worldwide, and it is caused by mutations in the two genes ERCC8, known as CSA, and ERCC6, commonly described as CSB, accounting for 20% and 80% of CS cases, respectively [1,2,3]
Pharyngeal pumping rates are a sensitive parameter of the functionality of a somatic tissue and decline rapidly in completely NER-deficient xpa1 mutant animals following UVB treatment [10,15]. csb-1 mutant animals show decreased pharyngeal pumping rates compared to wildtype animals at Day 2 of adulthood, which was accentuated with UV irradiation and progressed over the first 4 days of adulthood (Figure 1A)
To investigate whether C. elegans deficient for CSB-1 show signs of neurodegeneration, we examined the gentle touch response that is mediated by the mechanosensory neurons, posterior lateral microtubule cells (PLM), anterior lateral microtubule cells (ALM), and posterior ventral microtubule cell (PVM) [18]
Summary
Cockayne syndrome (CS) is an autosomal recessive genetic disorder with an occurrence of 2.5 cases per million births worldwide, and it is caused by mutations in the two genes ERCC8, known as CSA, and ERCC6, commonly described as CSB, accounting for 20% and 80% of CS cases, respectively [1,2,3]. The role of CSA and CSB in NER has been intensely investigated, the pleiotropic phenotypes associated with their dysfunction and the cellular and molecular defects underlying the symptoms are still poorly understood. A limited number of patients, most of which are compound heterozygotes, and the complexity and diversity of the symptoms challenge the study of the disease. It is unclear whether a single cellular process or whether a combination of events caused by various mechanisms could be contributing to the pathology differentially, synergistically and in cell type-specific ways [5]. Deciphering CS on a molecular level will provide further understanding of its underlying pathologies and the mechanisms of normal ageing, allowing for the design of possible intervention strategies
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