Over the past decade, phase transitions have emerged as a fundamental mechanism of cellular organization. In parallel, a wealth of evidence has accrued indicating that aberrations in phase ...transitions are early events in the pathogenesis of several neurodegenerative diseases. We review the key evidence of defects at multiple levels, from phase transition of individual proteins to the dynamic behavior of complex, multicomponent condensates in neurodegeneration. We also highlight two concepts, dynamical arrest and heterotypic buffering, that are key to understanding how pathological phase transitions relate to pleiotropic defects in cellular functions and the accrual of proteinaceous deposits at end-stage disease. These insights not only illuminate disease etiology but also are likely to guide the development of therapeutic interventions to restore homeostasis.
Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by degeneration of upper and lower motor neurons in the brain and spinal cord. The hallmark ...pathological feature in most cases of ALS is nuclear depletion and cytoplasmic accumulation of the protein TDP-43 in degenerating neurons. Consistent with this pattern of intracellular protein redistribution, impaired nucleocytoplasmic trafficking has emerged as a mechanism contributing to ALS pathology. Dysfunction in nucleocytoplasmic transport is also an emerging theme in physiological aging and other related neurodegenerative diseases, such as Huntington’s and Alzheimer’s diseases. Here we review transport through the nuclear pore complex, pointing out vulnerabilities that may underlie ALS and potentially contribute to this and other age-related neurodegenerative diseases.
Kim and Taylor provide an overview of transport through the nuclear pore complex, and they review the evidence suggesting that defects in nucleocytoplasmic transport contribute to ALS and perhaps other age-related neurodegenerative diseases.
What rational justification is there for conceiving of all living things as possessing inherent worth? InRespect for Nature, Paul Taylor draws on biology, moral philosophy, and environmental science ...to defend a biocentric environmental ethic in which all life has value. Without making claims for the moral rights of plants and animals, he offers a reasoned alternative to the prevailing anthropocentric view--that the natural environment and its wildlife are valued only as objects for human use or enjoyment.Respect for Natureprovides both a full account of the biological conditions for life--human or otherwise--and a comprehensive view of the complex relationship between human beings and the whole of nature.
This classic book remains a valuable resource for philosophers, biologists, and environmentalists alike--along with all those who care about the future of life on Earth. A new foreword by Dale Jamieson looks at how the original 1986 edition ofRespect for Naturehas shaped the study of environmental ethics, and shows why the work remains relevant to debates today.
The molecular processes that contribute to degenerative diseases are not well understood. Recent observations suggest that some degenerative diseases are promoted by the accumulation of nuclear or ...cytoplasmic RNA-protein (RNP) aggregates, which can be related to endogenous RNP granules. RNP aggregates arise commonly in degenerative diseases because RNA-binding proteins commonly self-assemble, in part through prion-like domains, which can form self-propagating amyloids. RNP aggregates may be toxic due to multiple perturbations of posttranscriptional control, thereby disrupting the normal “ribostasis” of the cell. This suggests that understanding and modulating RNP assembly or clearance may be effective approaches to developing therapies for these diseases.
Biomolecular condensation arising through phase transitions has emerged as an essential organizational strategy that governs many aspects of cell biology. In particular, the role of phase transitions ...in the assembly of large, complex ribonucleoprotein (RNP) granules has become appreciated as an important regulator of RNA metabolism. In parallel, genetic, histopathological and cell and molecular studies have provided evidence that disturbance of phase transitions is an important driver of neurological diseases, notably amyotrophic lateral sclerosis (ALS), but most likely also other diseases. Indeed, our growing knowledge of the biophysics underlying biological phase transitions suggests that this process offers a unifying mechanism to explain the numerous and diverse disturbances in RNA metabolism that have been observed in ALS and some related diseases - specifically, that these diseases are driven by disturbances in the material properties of RNP granules. Here, we review the evidence for this hypothesis, emphasizing the reciprocal roles in which disease-related protein and disease-related RNA can lead to disturbances in the material properties of RNP granules and consequent pathogenesis. Additionally, we review evidence that implicates aberrant phase transitions as a contributing factor to a larger set of neurodegenerative diseases, including frontotemporal dementia, certain repeat expansion diseases and Alzheimer disease.
Stress granules are membrane-less organelles composed of RNA-binding proteins (RBPs) and RNA. Functional impairment of stress granules has been implicated in amyotrophic lateral sclerosis, ...frontotemporal dementia, and multisystem proteinopathy—diseases that are characterized by fibrillar inclusions of RBPs. Genetic evidence suggests a link between persistent stress granules and the accumulation of pathological inclusions. Here, we demonstrate that the disease-related RBP hnRNPA1 undergoes liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by a low complexity sequence domain (LCD). While the LCD of hnRNPA1 is sufficient to mediate LLPS, the RNA recognition motifs contribute to LLPS in the presence of RNA, giving rise to several mechanisms for regulating assembly. Importantly, while not required for LLPS, fibrillization is enhanced in protein-rich droplets. We suggest that LCD-mediated LLPS contributes to the assembly of stress granules and their liquid properties and provides a mechanistic link between persistent stress granules and fibrillar protein pathology in disease.
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•hnRNPA1 undergoes spontaneous concentration-dependent liquid-liquid phase separation•Liquid-liquid phase separation is mediated by a low complexity sequence domain•Stress granules assemble in a RNA-binding protein concentration-dependent manner•Pathological fibrillization of hnRNPA1 is driven by liquid-liquid phase separation
Liquid-liquid phase separation by RNA-binding proteins harboring low complexity sequence domains is the molecular basis for stress granule assembly, and persistent stress granules promote pathological protein fibrillization.
Stress granules and P bodies are conserved cytoplasmic aggregates of nontranslating messenger ribonucleoprotein complexes (mRNPs) implicated in the regulation of mRNA translation and decay and are ...related to RNP granules in embryos, neurons, and pathological inclusions in some degenerative diseases. Using baker’s yeast, 125 genes were identified in a genetic screen that affected the dynamics of P bodies and/or stress granules. Analyses of such mutants, including CDC48 alleles, provide evidence that stress granules can be targeted to the vacuole by autophagy, in a process termed granulophagy. Moreover, stress granule clearance in mammalian cells is reduced by inhibition of autophagy or by depletion or pathogenic mutations in valosin-containing protein (VCP), the human ortholog of CDC48. Because mutations in VCP predispose humans to amyotrophic lateral sclerosis, frontotemporal lobar degeneration, inclusion body myopathy, and multisystem proteinopathy, this work suggests that autophagic clearance of stress granule related and pathogenic RNP granules that arise in degenerative diseases may be important in reducing their pathology.
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•Network of 125 genes identified affecting stress-granule and P body dynamics in yeast•Stress granules are cleared by autophagy in yeast and mammalian cells•Cdc48/VCP facilitates stress-granule clearance•Autophagy of related mRNP aggregates may help avoid degenerative pathology
Proteins linked to modulating stress-granule levels include key autophagy factors, and regulation of these RNP aggregates by autophagic clearance, involving VCP/Cdc48, is conserved in yeast and mammalian cells; this has implications for addressing these kinds of aggregates in neuronal pathologies.
Police shootings have become one of the most “visible and controversial” aspects of the criminal justice system . Yet, very little empirical effort has been devoted to understanding the underlying ...systemic vulnerabilities that likely contribute to these tragic outcomes. Using a randomized controlled experiment that incorporated a police firearms simulator and 306 active law enforcement officers, this study examined the effects of dispatch priming on an officer’s decision to use deadly force. The findings suggest that officers rely heavily on dispatched information in making the decision to pull the trigger when confronted with an ambiguously armed subject in a simulated environment. When the dispatched information was erroneous, it contributed to a significant increase in shooting errors. The results contribute to a broader understanding of officer decision-making within the context of police shootings and introduce the theoretical concepts of cognitive heuristics and human error to the research on police use of deadly force.
Stress granules are dynamic, reversible condensates composed of RNA and protein that assemble in eukaryotic cells in response to a variety of stressors and are normally disassembled after stress is ...removed. The composition and assembly of stress granules is well understood, but little is known about the mechanisms that govern disassembly. Impaired disassembly has been implicated in some diseases including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Using cultured human cells, we found that stress granule disassembly was context-dependent: Specifically in the setting of heat shock, disassembly required ubiquitination of G3BP1, the central protein within the stress granule RNA-protein network. We found that ubiquitinated G3BP1 interacted with the endoplasmic reticulum–associated protein FAF2, which engaged the ubiquitin-dependent segregase p97/VCP (valosin-containing protein). Thus, targeting of G3BP1 weakened the stress granule–specific interaction network, resulting in granule disassembly.
Genome damage and their defective repair have been etiologically linked to degenerating neurons in many subtypes of amyotrophic lateral sclerosis (ALS) patients; however, the specific mechanisms ...remain enigmatic. The majority of sporadic ALS patients feature abnormalities in the transactivation response DNA-binding protein of 43 kDa (TDP-43), whose nucleo-cytoplasmic mislocalization is characteristically observed in spinal motor neurons. While emerging evidence suggests involvement of other RNA/DNA binding proteins, like FUS in DNA damage response (DDR), the role of TDP-43 in DDR has not been investigated. Here, we report that TDP-43 is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with DDR and NHEJ factors, specifically acting as a scaffold for the recruitment of break-sealing XRCC4-DNA ligase 4 complex at DSB sites in induced pluripotent stem cell-derived motor neurons. shRNA or CRISPR/Cas9-mediated conditional depletion of TDP-43 markedly increases accumulation of genomic DSBs by impairing NHEJ repair, and thereby, sensitizing neurons to DSB stress. Finally, TDP-43 pathology strongly correlates with DSB repair defects, and damage accumulation in the neuronal genomes of sporadic ALS patients and in Caenorhabditis elegans mutant with TDP-1 loss-of-function. Our findings thus link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease, and suggest that DSB repair-targeted therapies may ameliorate TDP-43 toxicity-induced genome instability in motor neuron disease.
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