Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy

Abstract

ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADPribose from NAD þ to the target protein, and ADP-ribosylhydrolases, such as ADPRHL2, reverse the reaction. We used exome sequencing to identify five different bi-allelic pathogenic ADPRHL2 variants in 12 individuals from 8 families affected by a neurodegenerative disorder manifesting in childhood or adolescence with key clinical features including developmental delay or regression, seizures, ataxia, and axonal (sensori-)motor neuropathy. ADPRHL2 was virtually absent in available affected individuals' fibroblasts, and cell viability was reduced upon hydrogen peroxide exposure, although it was rescued by expression of wild-type ADPRHL2 mRNA as well as treatment with a PARP1 inhibitor. Our findings suggest impaired protein ribosylation as another pathway that, if disturbed, causes neurodegenerative diseases.

(ADP-ribosyl)hydrolases: structure, function, and biology

“…The increased sensitivity of human and mouse ARH3-deficient cells to hydrogen peroxide-induced cell death supports this theory (Tanuma et al 2016;. Loss-of-function mutations in ARH3 were linked to the pathogenesis of a rare recessive autosomal neurodegenerative disorder (Danhauser et al 2018;Ghosh et al 2018), suggesting that ARH3 contributes to the protection of neurons from endogenous ROS. In contrast, the mitochondrial function of ARH3 remains elusive, but current observations support two possibilities: First, ARH3 can degrade ADP-ribosylation artificially targeted to the mitochondrial matrix, and hence may be responsible for potential endogenous ADP-ribosylation in this compartment (Niere et al 2012).…”

ADP-ribosylation: from molecular mechanisms to human disease

“…ARH3 has specificity for both poly-ADP-ribose chains as well as mono-ADP-ribose moieties attached to serines (Abplanalp et al, 2017;Fontana et al, 2017), whereas TARG hydrolyses the ester linkage between mono-ADP-ribose and aspartate or glutamate side chains (Sharifi et al, 2013). ARH3 mutations are associated with neurodegenerative defects such as ataxia and febrile seizures, while TARG1 loss causes severe developmental delay, epilepsy and quadriplegia (Sharifi et al, 2013;Danhauser et al, 2018;Ghosh et al, 2018). Whereas TARG deficient cells shown signs of DNA-repair defects, a role for ARH3 in DNA damage re-sponses is speculative at this point, although serine has been recently established as the primary acceptor of DNA damage-induced ADP-ribosylation (Palazzo et al, 2018).…”

“…Whereas TARG deficient cells shown signs of DNA-repair defects, a role for ARH3 in DNA damage re-sponses is speculative at this point, although serine has been recently established as the primary acceptor of DNA damage-induced ADP-ribosylation (Palazzo et al, 2018). If excessive PAR formation, NAD + depletion and/or parthanatos are also involved in promoting the neurological defects seen in these patients, currently available catalytic PARP1 inhibitors may well be a viable therapeutic option (Danhauser et al, 2018;Ghosh et al, 2018).…”

Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair

“…Similar to defects in SSBR, aberrant ADP-ribose metabolism is also linked to neurodegeneration in humans. This is illustrated by the genetic disease childhood-onset, stress-induced, with variable ataxia and seizures (CONDSIAS), which is mutated in the ADPRHL2 gene encoding ARH3 [17][18][19] . That ARH3 mutations might trigger neurodegeneration by perturbing ADP-ribose metabolism during SSBR is consistent with reported involvement of this protein in degrading free poly(ADP-ribose) chains produced following H 2 O 2 -induced oxidative stress, a major inducer of SSBs, and by the protection against oxidative stress afforded in ARH3 −/− cells and mice by PARP inhibition 19,20 .…”