Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.
Title: Don't forget to be picky – selective autophagy of protein aggregates in neurodegenerative diseases
Authors: AnneSimonsen, ThomasWollert
Type: Review Article of Current Opinion in Cell Biology
The homeostasis of cells depends on the selective degradation of damaged or superfluous cellular components. Autophagy is the major pathway that recognizes such components, sequesters them in de novo formed autophagosomes and delivers them to lysosomes for degradation. The recognition of specific cargo and the biogenesis of autophagosomes involve a dedicated machinery of autophagy related (ATG) proteins. Intense research over the past decades has revealed insights into the function of autophagy proteins and mechanisms that govern cargo recognition. Other aspects including the molecular mechanisms involved in the onset of human diseases are less well understood. However, autophagic dysfunctions, caused by age related decline in autophagy or mutations in ATG proteins, are directly related to a large number of human pathologies including neurodegenerative disorders. Here, we review most recent discoveries and breakthroughs in selective autophagy and its relationship to neurodegeneration.
Access this article: https://doi.org/10.1016/j.ceb.2022.01.009
Title: Prion Protein Biology Through the Lens of Liquid-Liquid Phase Separation
Authors: AishwaryaAgarwal, SamratMukhopadhyay
Type: Review Article of Journal of Molecular Biology
●Conformational conversion of the prion protein (PrP) is involved in prion diseases.
●Liquid-liquid phase separation (LLPS) is associated with neurodegenerative diseases.
●PrP can undergo LLPS in the absence and the presence of nucleic acids.
●The N-terminal intrinsically disordered region of PrP is the primary driver of LLPS.
●LLPS might offer an alternative non-canonical pathway to promote PrP aggregation.
Conformational conversion of the α-helix-rich cellular prion protein into the misfolded, β-rich, aggregated, scrapie form underlies the molecular basis of prion diseases that represent a class of invariably fatal, untreatable, and transmissible neurodegenerative diseases. However, despite the extensive and rigorous research, there is a significant gap in the understanding of molecular mechanisms that contribute to prion pathogenesis. In this review, we describe the historical perspective of the development of the prion concept and the current state of knowledge of prion biology including structural, molecular, and cellular aspects of the prion protein. We then summarize the putative functional role of the N-terminal intrinsically disordered segment of the prion protein. We next describe the ongoing efforts in elucidating the prion phase behavior and the emerging role of liquid–liquid phase separation that can have potential functional relevance and can offer an alternate non-canonical pathway involving conformational conversion into a disease-associated form. We also attempt to shed light on the evolutionary perspective of the prion protein highlighting the potential role of intrinsic disorder in prion protein biology and summarize a few important questions associated with the phase transitions of the prion protein. Delving deeper into these key aspects can pave the way for a detailed understanding of the critical molecular determinants of the prion phase transition and its relevance to physiology and neurodegenerative diseases.
Access this article: https://doi.org/10.1016/j.jmb.2021.167368
Title: Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins
Authors: Julia E. Gerson, Hunter Linton, Jiazheng Xing, Alexandra B. Sutter, Fayth S. Kakos, Jaimie Ryou, Nyjerus Liggans, Lisa M. Sharkey, Nathaniel Safren, Henry L. Paulson, Magdalena I. Ivanova
Type: Article of Scientific Reports
The brain-expressed ubiquilins, UBQLNs 1, 2 and 4, are highly homologous proteins that participate in multiple aspects of protein homeostasis and are implicated in neurodegenerative diseases. Studies have established that UBQLN2 forms liquid-like condensates and accumulates in pathogenic aggregates, much like other proteins linked to neurodegenerative diseases. However, the relative condensate and aggregate formation of the three brain-expressed ubiquilins is unknown. Here we report that the three ubiquilins differ in aggregation propensity, revealed by in-vitro experiments, cellular models, and analysis of human brain tissue. UBQLN4 displays heightened aggregation propensity over the other ubiquilins and, like amyloids, UBQLN4 forms ThioflavinT-positive fibrils in vitro. Measuring fluorescence recovery after photobleaching (FRAP) of puncta in cells, we report that all three ubiquilins undergo liquid–liquid phase transition. UBQLN2 and 4 exhibit slower recovery than UBQLN1, suggesting the condensates formed by these brain-expressed ubiquilins have different compositions and undergo distinct internal rearrangements. We conclude that while all brain-expressed ubiquilins exhibit self-association behavior manifesting as condensates, they follow distinct courses of phase-separation and aggregation. We suggest that this variability among ubiquilins along the continuum from liquid-like to solid informs both the normal ubiquitin-linked functions of ubiquilins and their accumulation and potential contribution to toxicity in neurodegenerative diseases.
Access this article: https://doi.org/10.1038/s41598-020-78775-4
Title: Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease
Authors: Sandeep K. Rai, Adriana Savastano, Priyanka Singh, Samrat Mukhopadhyay, Markus Zweckstetter
Type: Review of Protein Science
Biomolecular condensation via liquid–liquid phase separation (LLPS) of intrinsically disordered proteins/regions (IDPs/IDRs), with and without nucleic acids, has drawn widespread interest due to the rapidly unfolding role of phase-separated condensates in a diverse range of cellular functions and human diseases. Biomolecular condensates form via transient and multivalent intermolecular forces that sequester proteins and nucleic acids into liquid-like membrane-less compartments. However, aberrant phase transitions into gel-like or solid-like aggregates might play an important role in neurodegenerative and other diseases. Tau, a microtubule-associated neuronal IDP, is involved in microtubule stabilization, regulates axonal outgrowth and transport in neurons. A growing body of evidence indicates that tau can accomplish some of its cellular activities via LLPS. However, liquid-to-solid transition resulting in the abnormal aggregation of tau is associated with neurodegenerative diseases. The physical chemistry of tau is crucial for governing its propensity for biomolecular condensation which is governed by various intermolecular and intramolecular interactions leading to simple one-component and complex multi-component condensates. In this review, we aim at capturing the current scientific state in unveiling the intriguing molecular mechanism of phase separation of tau. We particularly focus on the amalgamation of existing and emerging biophysical tools that offer unique spatiotemporal resolutions on a wide range of length- and time-scales. We also discuss the link between quantitative biophysical measurements and novel biological insights into biomolecular condensation of tau. We believe that this account will provide a broad and multidisciplinary view of phase separation of tau and its association with physiology and disease.
Access this article: https://doi.org/10.1002/pro.4093
Title: Roles of non-canonical structures of nucleic acids in cancer and neurodegenerative diseases
Authors: Hisae Tateishi-Karimata, Naoki Sugimoto
Type: Review of Nucleic Acids Research
Cancer and neurodegenerative diseases are caused by genetic and environmental factors. Expression of tumour suppressor genes is suppressed by mutations or epigenetic silencing, whereas for neurodegenerative disease-related genes, nucleic acid-based effects may be presented through loss of protein function due to erroneous protein sequences or gain of toxic function from extended repeat transcripts or toxic peptide production. These diseases are triggered by damaged genes and proteins due to lifestyle and exposure to radiation. Recent studies have indicated that transient, non-canonical structural changes in nucleic acids in response to the environment can regulate the expression of disease-related genes. Non-canonical structures are involved in many cellular functions, such as regulation of gene expression through transcription and translation, epigenetic regulation of chromatin, and DNA recombination. Transcripts generated from repeat sequences of neurodegenerative disease-related genes form non-canonical structures that are involved in protein transport and toxic aggregate formation. Intracellular phase separation promotes transcription and protein assembly, which are controlled by the nucleic acid structure and can influence cancer and neurodegenerative disease progression. These findings may aid in elucidating the underlying disease mechanisms. Here, we review the influence of non-canonical nucleic acid structures in disease-related genes on disease onset and progression.
Access this article: https://doi.org/10.1093/nar/gkab580