TDP-43 is a nuclear RNA-binding protein whose cytoplasmic accumulation is the pathological hallmark of amyotrophic lateral sclerosis (ALS). For a better understanding of this devastating disorder at the molecular level, it is important to identify cellular pathways involved in the clearance of detrimental TDP-43. Using a yeast model system, we systematically analyzed to which extent TDP-43-triggered cytotoxicity is modulated by conserved lysosomal clearance pathways. We observed that the lysosomal fusion machinery and the endolysosomal pathway, which are crucial for proper lysosomal function, were pivotal for survival of cells exposed to TDP-43. Interestingly, TDP-43 itself interfered with these critical TDP-43 clearance pathways. In contrast, autophagy played a complex role in this process. It contributed to the degradation of TDP-43 in the absence of endolysosomal pathway activity, but its induction also enhanced cell death. Thus, TDP-43 interfered with lysosomal function and its own degradation via lysosomal pathways, and triggered lethal autophagy. We propose that these effects critically contribute to cellular dysfunction in TDP-43 proteinopathies.

Heavy rainfall causes flooding of natural ecosystems as well as farmland, negatively affecting plant performance. While the responses of the wild model organism Arabidopsis thaliana to such stress conditions is well understood, little is known about the responses of its relative, the important oil crop plant Brassica napus. For the first time, we analyzed the molecular response of Brassica napus seedlings to full submergence in a natural light–dark cycle. We used two cultivars in this study, a European hybrid cultivar and an Asian flood‐tolerant cultivar. Despite their genomic differences, those genotypes showed no major differences in their responses to submergence. The molecular responses to submergence included the induction of defense‐ and hormone‐related pathways and the repression of biosynthetic processes. Furthermore, RNAseq revealed a strong carbohydrate‐starvation response under submergence in daylight, which corresponded with a fast depletion of sugars. Consequently, both B. napus cultivars exhibited a strong growth repression under water, but there was no indication of a low‐oxygen response. The ability of the European hybrid cultivar to form a short‐lived leaf gas film neither increased underwater net photosynthesis, underwater dark respiration nor growth during submergence. Due to the high sensitivity of both cultivars, the analysis of other cultivars or related species with higher submergence tolerance is required in order to improve flood tolerance of this crop species. One major target could be the improvement of underwater photosynthesis efficiency in order to enhance submergence survival.

The accumulation of protein aggregates in neurons is a typical pathological hallmark of the motor neuron disease amyotrophic lateral sclerosis (ALS) and of frontotemporal dementia (FTD).First, it interferes with its own degradation via this pathway, resulting in TDP-43 accumulation. Second, it affects vacuolar proteolytic activity, which requires endosomal-vacuolar trafficking. We speculate that the latter contributes to aberrant autophagy. In sum, we propose that ameliorating endolysosomal pathway activity enhances cell survival in TDP-43-associated diseases.Our study highlights the pivotal role of endolysosomal pathway activity in TDP-43 proteinopathies. Whereas previous studies focused on the role of autophagy in the clearance of cytotoxic TDP-43, we propose that the endolysosomal pathway is more important than autophagy for the survival of cells accumulating detrimental TDP-43. In both pathways, protein substrates (such as TDP-43) are sequestered into vesicles, either multivesicular bodies (MVBs) or autophagosomes (Figure 1). These vesicles fuse with the lysosomal membrane and subsequently release their content into the lysosomal lumen, where protein degradation occurs via proteases such as Pep4/Cathepsin D. Both vesicular pathways are interconnected. In mammalian cells (but not in yeast), some MVBs fuse with autophagosomes, leading to the formation of amphisomes which then fuse with lysosomes. Moreover, the endolysosomal pathway is required for directing important lysosomal proteases, thus decisively contributing to proteolytic capacity of this organelle.Our study raises a number of questions regarding TDP-43 degradation and cytotoxicity. For instance, in cells accumulating cytoplasmic TDP-43, different types of potentially cytotoxic TDP-43 species can be expected, e.g., mon-________________________ MICROREVIEW on: Leibiger C, Deisel J, Aufschnaiter A, Ambros S, Tereshchenko M, Verheijen BM, Büttner S and Braun RJ (2018).TDP-43 controls lysosomal pathways thereby determining its own clearance and cytotoxicity. Hum Mol Genet.

Waterlogging is one major stress for crops and causes multiple problems for plants, for example low gas diffusion, changes in redox potential and accumulation of toxic metabolites. Brassica napus is an important oil crop with high waterlogging sensitivity, which may cause severe yield losses. Its reactions to the stress are not fully understood. In this work the transcriptional response of rapeseed to one aspect of waterlogging, hypoxia in the root zone, was analyzed by RNAseq, including two rapeseed cultivars from different origin, Avatar from Europe and Zhongshuang 9 from Asia. Both cultivars showed a high number of differentially expressed genes in roots after 4 and 24 h of hypoxia. The response included many well-known hypoxia-induced genes such as genes coding for glycolytic and fermentative enzymes, and strongly resembled the hypoxia response of the model organism Arabidopsis thaliana. The carbohydrate status of roots, however, was minimally affected by root hypoxia, with a tendency of carbohydrate accumulation rather than a carbon starvation. Leaves did not respond to the root stress after a 24-h treatment. In agreement with the gene expression data, subsequent experiments with soil waterlogging for up to 14 days revealed no differences in response or tolerance to waterlogging between the two genotypes used in this study. Interestingly, using a 0.1% starch solution for waterlogging, which caused a lowered soil redox potential, resulted in much stronger effects of the stress treatment than using pure water suggesting a new screening method for rapeseed cultivars in future experiments.