The expression of the distal dystrophin isoforms Dp140 and Dp71 in the human epileptic hippocampus in relation to cognitive functioning

Abstract

Dystrophin is an important protein within the central nervous system. The absence of dystrophin, characterizing Duchenne muscular dystrophy (DMD), is associated with brain related comorbidities such as neurodevelopmental (e.g., cognitive and behavioural) deficits and epilepsy. Especially mutations in the downstream part of the DMD gene affecting the dystrophin isoforms Dp140 and Dp71 are found to be associated with cognitive deficits. However, the function of Dp140 is currently not well understood and its expression pattern has previously been implicated to be developmentally regulated. Therefore, we evaluated Dp140 and Dp71 expression in human hippocampi in relation to cognitive functioning in patients with drug-resistant temporal lobe epilepsy (TLE) and post-mortem controls. Hippocampal samples obtained as part of epilepsy surgery were quantitatively analyzed by Western blot and correlations with neuropsychological test results (i.e., memory and intelligence) were examined. First, we demonstrated that the expression of Dp140 does not appear to differ across different ages throughout adulthood. Second, we identified an inverse correlation between memory loss (i.e., verbal and visual memory), but not intelligence (i.e., neither verbal nor performance), and hippocampal Dp140 expression. Finally, patients with TLE appeared to have similar Dp140 expression levels compared to post-mortem controls without neurological disease. Dp140 may thus have a function in normal cognitive (i.e., episodic memory) processes.

Dystrophin deficiency affects human astrocyte properties and response to damage

“…In contrast, we found expres- Importantly, Dp (A) does not recognize a micro-dystrophin that lacks the C-terminus, thus demonstrating specificity (Montanaro, personal communication). Interestingly, bands of similar sizes have been observed in western blots for dystrophin in human and rat brains in other studies, though this was not commented on by the authors (Hendriksen et al, 2016;Hoogland et al, 2018). There is evidence for several short Dp71 variants that contain the C-terminus, including a F I G U R E 9 Heatmaps show significant down-regulation of genes involved in cell adhesion and extracellular matrix (ECM) receptor interaction.…”

“…The role of dystrophin has been extensively studied in muscle, where the full-length isoforms play an important structural role by connecting the cell cytoskeleton to the extracellular matrix (Blake et al, 2002). In contrast, relatively little is known about the role of the different isoforms in the brain, particularly in humans (Hoogland et al, 2018). It is still debated whether the neural deficits observed in DMD children are entirely acquired during prenatal development, hence "fixed," or there is some progression of the neural phenotype at least in the early years when the CNS is still highly plastic (Bagdatlioglu et al, 2020).…”

In vivo cerebellar circuit function is disrupted in an mdx mouse model of Duchenne muscular dystrophy

“…One possibility is that the cerebellum promotes coherent activity between cortical brain regions; an example could be an adjustment in hippocampal-prefrontal cortex coherence upon Purkinje cell activation (McAfee et al, 2019). Interestingly, the hippocampus (Hoogland et al, 2019;Krasowska et al, 2014;Miranda et al, 2015Miranda et al, , 2016 and prefrontal cortex (Suzuki et al, 2017) exhibit abnormalities in human DMD and mdx mice. It is therefore tantalizing to hypothesize that the decreased Purkinje cell simple spike output and the more variable cerebellar nuclear output in mdx mice could contribute to the motor or cognitive deficits reported in individuals with DMD.…”

Epigenetic modifications in muscle regeneration and progression of Duchenne muscular dystrophy

“…2a), and protein arginine methyltransferases (PRMTs). The first group includes, among others, the following families: suppressor of variegation 3-9 (SUV39), e.g., G9a methyltransferase that methylates lysine 9 of histone H3 (H3K9); enhancer of zeste homolog (EZH); SET1, which includes lysine methyltransferase 2A (MLL); SET2; SET7 and suppressor of variegation [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. The group of arginine methyltransferases comprises of ten mammalian PRMTs (PRMT1-10) that have been identified to date [61].…”

“…Duchenne muscular dystrophy (DMD, OMIM 310200), the most severe and the most common adult form of muscular dystrophy in humans, is caused by a lack of functional dystrophin due to mutations in the dystrophin gene (DMD) [1,2]. This largest gene in the human genome (> 2.5 Mbp) gives rise to several transcripts that encode protein isoforms ranging in size from 40 to 427 kDa, which are variously distributed in many cell types [3][4][5][6][7][8][9][10][11]. Because DMD is located on the X chromosome (Xp21.2 region), the disease primarily affects boys with estimates of incidence ranging from one in every 3500 to more recent estimates of 1:5000 live births [12][13][14].…”