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Dipeptide repeat proteins (DPRs) occur via repeat-associated non-AUG (RAN) translation. In this issue of Neuron, McEachin et al. (2020) show that the aggregation-prone poly(GA)-rich chimeric DPRs determine divergent poly(GP) mediated pathology between C9ALS/FTD and SCA36.

Insects adapt to plant protease inhibitors (PIs) present in their diet by differentially regulating multiple digestive proteases. However, mechanisms regulating protease gene expression in insects are largely enigmatic. Ingestion of multi-domain recombinant Capsicum annuum protease inhibitor-7 (CanPI-7) arrests growth and development of Helicoverpa armigera (Lepidoptera: Noctuidae). Using de novo RNA sequencing and proteomic analysis, we examined the response of H. armigera larvae fed on recombinant CanPI-7 at different time intervals. Here, we present evidence supporting a dynamic transition in H. armigera protease expression on CanPI-7 feeding with general down-regulation of protease genes at early time points (0.5 to 6 h) and significant up-regulation of specific trypsin, chymotrypsin and aminopeptidase genes at later time points (12 to 48 h). Further, coexpression of H. armigera endogenous PIs with several digestive protease genes were apparent. In addition to the differential expression of endogenous H. armigera PIs, we also observed a distinct novel isoform of endogenous PI in CanPI-7 fed H. armigera larvae. Based on present and earlier studies, we propose potential mechanism of protease regulation in H. armigera and subsequent adaptation strategy to cope with anti-nutritional components of plants.

Neurotrophin receptors of the Trk family promote neuronal survival. The signal transduction of Trk receptors is regulated by endosomal trafficking. Monoubiquitination of receptor tyrosine kinases is an established signal for sorting of internalized receptors to late endosomes. The NGF receptor TrkA is sorted to late endosomes and undergoes ubiquitination, indicating a so far undefined regulatory role of proteasomal activity in the trafficking of TrkA. Surprisingly, we found that proteasomal inhibition alters the trafficking of TrkA from the late endosomal sorting pathway to the recycling pathway. Many neurodegenerative diseases are associated with impaired proteasomal activity. Thus, our study suggests that missorting of neurotrophic receptors might contribute to neuronal death in those neurodegenerative diseases that are known to be associated with impaired proteasomal function.

Neurotrophins transmit signals retrogradely from synapses to cell bodies by two different types of surface receptors, p75NTR and Trks. Compared to TrkA, the function of p75NTR in nerve growth factor (NGF) endocytosis is less clear, and it is unknown whether p75NTR by itself may internalize other neurotrophins besides NGF. We directly compared TrkA and p75NTR for their ability to internalize NGF, and we also examined the endocytosis of iodinated brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) by p75NTR. Cells expressing solely TrkA internalized NGF more efficiently than cells expressing p75NTR. Surprisingly, cells expressing only p75NTR internalized far more BDNF or NT3 than NGF. Moreover, p75NTR was more important for surface binding than for intracellular accumulation of each neurotrophin. Finally, we established a mechanistic role for the clathrin pathway in p75NTR endocytosis. Our results suggest that p75NTR may have multiple roles in different subcellular locations, functioning both at the cell surface and also within endocytic compartments. © 2004 Elsevier Inc. All rights reserved., This study was supported by a grant from the Swiss National Science Foundation