Due to environmental insult or innate genetic deficiency, protein folding environments of the mitochondrial matrix are prone to dysregulation, prompting the activation of a specific organellar stress-response mechanism, the mitochondrial unfolded protein response (UPR). In , mitochondrial damage leads to nuclear translocation of the ATFS-1 transcription factor to activate the UPR After short-term acute stress has been mitigated, the UPR is eventually suppressed to restore homeostasis to hermaphrodites. In contrast, and reflective of the more chronic nature of progressive neurodegenerative disorders such as Parkinson's disease (PD), here, we report the consequences of prolonged, cell-autonomous activation of the UPR in dopaminergic neurons. We reveal that neuronal function and integrity decline rapidly with age, culminating in activity-dependent, non-apoptotic cell death. In a PD-like context wherein transgenic nematodes express the Lewy body constituent protein α-synuclein (αS), we not only find that this protein and its PD-associated disease variants have the capacity to induce the UPR, but also that coexpression of αS and ATFS-1-associated dysregulation of the UPR synergistically potentiate dopaminergic neurotoxicity. This genetic interaction is in parallel to mitophagic pathways dependent on the homolog, which is necessary for cellular resistance to chronic malfunction of the UPR Given the increasingly recognized role of mitochondrial quality control in neurodegenerative diseases, these studies illustrate, for the first time, an insidious aspect of mitochondrial signaling in which the UPR pathway, under disease-associated, context-specific dysregulation, exacerbates disruption of dopaminergic neurons , resulting in the neurodegeneration characteristic of PD. Disruptions or alterations in the activation of pathways that regulate mitochondrial quality control have been linked to neurodegenerative diseases due in part to the central role of mitochondria in metabolism, ROS regulation, and proteostasis. The extent to which these pathways, including the mitochondrial unfolded protein response (UPR) and mitophagy, are active may predict severity and progression of these disorders, as well as sensitivity to compounding stressors. Furthermore, therapeutic strategies that aim to induce these pathways may benefit from increased study into cellular responses that arise from long-term or ectopic stimulation, especially in neuronal compartments. By demonstrating the detrimental consequences of prolonged cellular activation of the UPR, we provide evidence that this pathway is not a universally beneficial mechanism because dysregulation has neurotoxic consequences.

Liquid-liquid phase separation or LLPS of proteins is a field of mounting importance and the value of quantitative kinetic and thermodynamic characterization of LLPS is increasingly recognized. We present a method, Capflex, which allows rapid and accurate quantification of key parameters for LLPS: Dilute phase concentration, relative droplet size distributions, and the kinetics of droplet formation and maturation into amyloid fibrils. The binding affinity between the polypeptide undergoing LLPS and LLPS-modulating compounds can also be determined. We apply Capflex to characterize the LLPS of Human DEAD-box helicase-4 and the coacervate system ssDNA/RP3. Furthermore, we study LLPS and the aberrant liquid-to-solid phase transition of α-synuclein. We quantitatively measure the decrease in dilute phase concentration as the LLPS of α-synuclein is followed by the formation of Thioflavin-T positive amyloid aggregates. The high information content, throughput and the versatility of Capflex makes it a valuable tool for characterizing biomolecular LLPS.

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A group of nine achondritic meteorites, the SNC-meteorites, are believed to be rocks from the planet Mars. With the planned exploration of Mars in mind, perhaps including in situ Mössbauer spectroscopy, the study of the SNC-meteorites takes on a specific significance. We have performed Mössbauer spectroscopy of specimens from one of these meteorites, Zagami. Surprisingly, the Mössbauer spectra of two separate samples from Zagami are very different. One of the samples shows no olivine, in agreement with the description of the meteorite Zagami in the literature. The other sample shows that about 23% of the iron is placed in olivine, and X-ray diffraction analysis confirms the existence of olivine as a major component in this sample. We are thus forced to conclude that the meteorite Zagami is inhomogeneous on a macroscopic scale. This result has evidently implications for the understanding of the igneous rocks on Mars, and thus for the interpretation of their Mössbauer spectra.