Lammens, M. | Search bioRxiv

bioRxiv2020

Uneven distribution of Purkinje cell injury in the cerebellar vermis of term neonates with hypoxic-ischemic encephalopathy

IntroductionIn term neonates with hypoxic-ischemic encephalopathy (HIE), cerebellar injury is becoming more and more acknowledged. Animal studies demonstrated that Purkinje cells (PCs) are especially vulnerable for hypoxic-ischemic injury. In neonates, however, the extent and pattern of PC injury has not been investigated. The aim of this study was to determine the distribution of PC injury in the cerebellar vermis of term born neonates with HIE. MethodsTerm born neonates with HIE that underwent post-mortem autopsy of the cerebellar vermis were included. Haematoxylin & Eosin (H&E) stained sections of the vermis were used to determine total PC count and morphology (normal, abnormal or non-classified) at the bases and crown of the folia and of the lobules in both the anterior and posterior lobes. Differences in PC count and PC morphology between the anterior and posterior lobe and between the bases and crown were calculated using the paired samples T-test or Wilcoxon-signed rank test. ResultsThe total number of PCs were significantly higher at the crown compared to the bases (p<0.001) irrespective of the precise location. Besides, PCs at the bases more often had an abnormal morphology. No significant difference between the total number of PCs in the anterior and posterior lobe was observed. ConclusionThe abnormal PC count and morphology in term neonates with HIE resembles supratentorial ulegyria.

neuroscience↗

bioRxiv2018

Mutations in nucleoporin NUP88 cause lethal fetal akinesia deformation sequence

Nucleoporins build the nuclear pore complex (NPC), which, as sole gate for nuclear-cytoplasmic exchange, are of outmost importance for normal cell function. Defects in the process of nucleocytoplasmic transport or in its machinery have been frequently described in human diseases, such as cancer and neurodegenerative disorders, but only in a few cases of developmental disorders. Here we report biallelic mutations in the nucleoporin NUP88 as a novel cause of lethal fetal akinesia deformation sequence (FADS) in two families. FADS comprises a spectrum of clinically and genetically heterogeneous disorders with congenital malformations related to impaired fetal movement. We show that genetic disruption of nup88 in zebrafish results in pleiotropic developmental defects reminiscent of those seen in affected human fetuses, including locomotor defects as well as defects at neuromuscular junctions. Phenotypic alterations become visible at distinct developmental stages, both in affected human fetuses and in zebrafish, whereas early stages of development are apparently normal. The zebrafish phenotypes caused by nup88 deficiency are only rescued by expressing wild-type nup88 and not the disease-linked mutant forms of nup88. Furthermore, using human and mouse cell lines as well as immunohistochemistry on fetal muscle tissue, we demonstrate that NUP88 depletion affects rapsyn, a key regulator of the muscle nicotinic acetylcholine receptor at the neuromuscular junction. Together, our studies provide the first characterization of NUP88 in vertebrate development, expand our understanding of the molecular events causing FADS, and suggest that variants in NUP88 should be investigated in cases of FADS.

cell biology↗