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Abstract TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL 1 gene harbors a copy of the human endogenous retrovirus HML-2, whose overexpression contributes to ALS pathogenesis. Here we show that ASRGL1 expression was diminished in ALS brain samples by RNA sequencing, immunohistochemistry, and western blotting. TDP-43 and ASRGL1 colocalized in neurons but, in the absence of ASRGL1, TDP-43 aggregated in the cytoplasm. TDP-43 was found to be prone to isoaspartate formation and a substrate for ASRGL1. ASRGL1 silencing triggered accumulation of misfolded, fragmented, phosphorylated and mislocalized TDP-43 in cultured neurons and motor cortex of female mice. Overexpression of ASRGL1 restored neuronal viability. Overexpression of HML-2 led to ASRGL1 silencing. Loss of ASRGL1 leading to TDP-43 aggregation may be a critical mechanism in ALS pathophysiology.

The in vivo pathogenesis of the blinding retinal degeneration choroideremia is visualized, which reveals enlarged and area-disrupted retinal pigment epithelial cells, providing evidence for polymegathism in choroideremia.

Matson et al. performed single nucleus sequencing of the “spared” spinal cord tissue distal to an injury in mice. They found that spinocerebellar neurons expressed a pro-regenerative gene signature and showed axon outgrowth after injury.

Murray et al. present a multiplexed fluorescence-based immunohistochemistry approach and use it to screen up to 100 protein markers in the human olfactory bulb from neurologically healthy, Alzheimer’s, and Parkinson’s disease patients. In doing so, they identify differentially expressed biomarkers in Alzheimer’s, and Parkinson’s disease.

The neurological effects of Ebola disease in the acute stage are not well-described. Here, the authors use longitudinal in vivo neuroimaging and immunohistochemistry to assess pathological changes in the central nervous system in a non-human primate model of Ebola virus infection.

It is challenging to map complex processes in brain tissue. Here the authors report a toolkit enabling large-scale multiplexed IHC and automated cell classification whereby they use a conventional epifluorescence microscope and deep neural networks to phenotype all major cell classes of the brain.

Spermatogonial stem cells have the dual capacity to self-renew and differentiate into mature spermatozoa. Here, using transcriptome analyses of juvenile testes in gene-edited mice, the authors demonstrate that PRAMEF12 is required to maintain germ cell homeostasis and promote their differentiation.

Abstract Protein SUMOylation is a dynamic post-translational modification shown to be involved in a diverse set of physiologic processes throughout the cell. SUMOylation has also been shown to play a role in the pathobiology of myriad cancers, one of which is glioblastoma multiforme (GBM). As such, the clinical significance and therapeutic utility offered via the selective control of global SUMOylation is readily apparent. There are, however, relatively few known/effective inhibitors of global SUMO-conjugation. Herein we describe the identification of topotecan as a novel inhibitor of global SUMOylation. We also provide evidence that inhibition of SUMOylation by topotecan is associated with reduced levels of CDK6 and HIF-1α, as well as pronounced changes in cell cycle progression and cellular metabolism, thereby highlighting its putative role as an adjuvant therapy in defined GBM patient populations.