Behavioural Characterisation of Macrod1 and Macrod2 Knockout Mice

Abstract

Adenosine diphosphate ribosylation (ADP-ribosylation; ADPr), the addition of ADP-ribose moieties onto proteins and nucleic acids, is a highly conserved modification involved in a wide range of cellular functions, from viral defence, DNA damage response (DDR), metabolism, carcinogenesis and neurobiology. Here we study MACROD1 and MACROD2 (mono-ADP-ribosylhydrolases 1 and 2), two of the least well-understood ADPr-mono-hydrolases. MACROD1 has been reported to be largely localized to the mitochondria, while the MACROD2 genomic locus has been associated with various neurological conditions such as autism, attention deficit hyperactivity disorder (ADHD) and schizophrenia; yet the potential significance of disrupting these proteins in the context of mammalian behaviour is unknown. Therefore, here we analysed both Macrod1 and Macrod2 gene knockout (KO) mouse models in a battery of well-defined, spontaneous behavioural testing paradigms. Loss of Macrod1 resulted in a female-specific motor-coordination defect, whereas Macrod2 disruption was associated with hyperactivity that became more pronounced with age, in combination with a bradykinesia-like gait. These data reveal new insights into the importance of ADPr-mono-hydrolases in aspects of behaviour associated with both mitochondrial and neuropsychiatric disorders.

Multivariate genome-wide association study on tissue-sensitive diffusion metrics identifies key molecular pathways for axonal growth, synaptogenesis, and astrocyte-mediated neuroinflammation

“…The association signals for rs6079582 show strong regional enrichment in the cerebellum white matter (Figure 2G-H), implicating its relationship with motor functions. A recent knockout mouse experiment has shown that knocking out the Macrod1 and Macrod2 would lead to disruption in Adenosine diphosphate ribosylation-mono-hydrolases, resulting in motor-coordination defect and age-dependent hyperactivities 40 , corroborate with what we found here.…”

Genome-wide association study of population-standardised cognitive performance phenotypes in a rural South African community

“…Rare and de novo CNV within this gene have been observed in ADHD patients 88 . Knockout mice exhibited hyperactivity which increased with age despite slower observed movement and unusual sleep patterns similar to that seen in ADHD 89 . The most reported SNP for this locus, rs4141463, reached genomewide significance for association with autism spectrum disorder (ASD) in a European study but was neither replicated in a later European study, nor in a study of Han Chinese [90][91][92] .…”

The Making and Breaking of Serine-ADP-Ribosylation in the DNA Damage Response

“…ADP-ribosylation refers to the transfer of ADP-ribose (ADPr) moiety from NAD + onto substrate proteins or nucleic acids by enzymes termed (ADP-ribosyl)transferases (ARTs; Figure 1 ; Liu and Yu, 2015 ; Wei and Yu, 2016 ; Munnur and Ahel, 2017 ; Zarkovic et al, 2018 ; Munnur et al, 2019 ; Groslambert et al, 2021 ). ADP-ribosylation can occur as mono- or poly(ADP-ribosyl)ation (MARylation or PARylation, respectively) and is a highly conserved and widespread posttranslational modification (PTM) that controls many cellular processes, including cell proliferation and differentiation, the cellular stress response, maintenance of genome stability, behavior, viral infection, and microbial metabolism ( Perina et al, 2014 ; Wei and Yu, 2016 ; Cohen and Chang, 2018 ; Palazzo et al, 2019 ; Crawford et al, 2021 ; Mikolčević et al, 2021 ). Proteins participating in ADPr signaling are often described in terms of “writers,” i.e., ARTs, “readers” that contain ADPr-binding domains, and “erasers” which modify or remove the ADP-ribosylation signal ( Gupte et al, 2017 ).…”