Stress granule assembly in vivo is deficient in the CNS of mutant TDP-43 ALS mice.

Responding effectively to external stress is crucial for neurons. Defective stress granule dynamics has been hypothesized as one of the pathways that renders motor neurons in amyotrophic lateral sclerosis (ALS) more prone to early death. Specifically, it is thought that stress granules seed the cytoplasmic TDP-43 inclusions that are observed in the neurons of most ALS patients, as well as ~50% of all frontotemporal dementia (FTD) patients. In this study, we tested this hypothesis in an intact mammalian nervous system. We established an in vivo heat stress paradigm in mice that effectively triggers the eIF2α pathway and the formation of stress granules in the CNS. In non-transgenic mice, we report an age-dependent decline in the formation of heat-induced stress granules, with 18-month-old animals showing a significant impairment. Furthermore, although neuronal stress granules were robustly observed in non-transgenic mice and SOD1G93A mice, they were largely absent in age-matched TDP-43M337V animals. The observed defect in stress granule formation in TDP-43M337V mice correlated with deficits in expression of key protein components typically required for phase separation. Lastly, while TDP-43 was not localized to stress granules, we observed complete nuclear depletion of TDP-43 in a subset of neurons, with the highest proportion being in the TDP-43M337V mice. Overall, our results indicate that mutant TDP-43 expression is associated with defective stress granule assembly and increased TDP-43 nuclear depletion in the mammalian nervous system, which could be relevant to ALS/FTD pathogenesis.

The multi-functional RNA-binding protein G3BP1 and its potential implication in neurodegenerative disease.

Ras-GTPase-activating protein (GAP)-binding protein 1 (G3BP1) is a multi-functional protein that is best known for its role in the assembly and dynamics of stress granules. Recent studies have highlighted that G3BP1 also has other functions related to RNA metabolism. In the context of disease, G3BP1 has been therapeutically targeted in cancers because its over-expression is correlated with proliferation of cancerous cells and metastasis. However, evidence suggests that G3BP1 is essential for neuronal development and possibly neuronal maintenance. In this review, we will examine the many functions that are carried out by G3BP1 in the context of neurons and speculate how these functions are critical to the progression of neurodegenerative diseases. Additionally, we will highlight the similarities and differences between G3BP1 and the closely related protein G3BP2, which is frequently overlooked. Although G3BP1 and G3BP2 have both been deemed important for stress granule assembly, their roles may differ in other cellular pathways, some of which are specific to the CNS, and presents an opportunity for further exploration.

Consequences of cytochrome c oxidase assembly defects for the yeast stationary phase.

The assembly of cytochrome c oxidase (COX) is essential for a functional mitochondrial respiratory chain, although the consequences of a loss of assembled COX at yeast stationary phase, an excellent model for terminally differentiated cells in humans, remain largely unexamined. In this study, we show that a wild-type respiratory competent yeast strain at stationary phase is characterized by a decreased oxidative capacity, as seen by a reduction in the amount of assembled COX and by a decrease in protein levels of several COX assembly factors. In contrast, loss of assembled COX results in the decreased abundance of many mitochondrial proteins at stationary phase, which is likely due to decreased membrane potential and changes in mitophagy. In addition to an altered mitochondrial proteome, COX assembly mutants display unexpected changes in markers of cellular oxidative stress at stationary phase. Our results suggest that mitochondria may not be a major source of reactive oxygen species at stationary phase in cells lacking an intact respiratory chain.

Altered stress granule disassembly: links to neurodegenerative disease?

A recent study by Gwon et al. identified context-specific ubiquitination of G3BP1 as critical for stress granule disassembly via VCP and the adaptor FAF2. This study provides new insights into stress granule dynamics, with potential implications for neurodegenerative disease.

hnRNP A1B, a Splice Variant of HNRNPA1, Is Spatially and Temporally Regulated.

RNA binding proteins (RBPs) play a key role in cellular growth, homoeostasis and survival and are tightly regulated. A deep understanding of their spatiotemporal regulation is needed to understand their contribution to physiology and pathology. Here, we have characterized the spatiotemporal expression pattern of hnRNP A1 and its splice variant hnRNP A1B in mice. We have found that hnRNP A1B expression is more restricted to the CNS compared to hnRNP A1, and that it can form an SDS-resistant dimer in the CNS. Also, hnRNP A1B expression becomes progressively restricted to motor neurons in the ventral horn of the spinal cord, compared to hnRNP A1 which is more broadly expressed. We also demonstrate that hnRNP A1B is present in neuronal processes, while hnRNP A1 is absent. This finding supports a hypothesis that hnRNP A1B may have a cytosolic function in neurons that is not shared with hnRNP A1. Our results demonstrate that both isoforms are differentially expressed across tissues and have distinct localization profiles, suggesting that the two isoforms may have specific subcellular functions that can uniquely contribute to disease progression.