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The outer mitochondrial membrane translocator protein (TSPO) mediates several mitochondrial functions and binds cholesterol with a high affinity. Here the authors use solid-state NMR to show that cholesterol binding to TSPO results in allosteric changes that modulate TSPO oligomerization.

Through structural and biochemical analyses, the authors uncover and Hsp90-independent pathway through which the co-chaperones p23 and the p23-FKBP51 complex modulate tau aggregation, a key feature of Alzheimer’s disease.

In vitro assays and high-resolution microscopy show that Pol II CTD undergoes length-dependent liquid phase separation and controls Pol II clustering and mobility in human cells.

Here, the authors demonstrate that mutations in the FG repeats of Nup98 significantly reduce its self-association capabilities and present a cryoEM structure exhibiting higher stability per residue then previously observed, suggesting spatial variations in self-association.

The authors show that acetylation enhances the aggregation of 3R tau, while blocking the aggregation of 4R tau, providing a molecular basis for disease- and isoform-specific tau deposition.

The structure of synapses is critical for brain function. Yu et al. show how the synaptic vesicle protein synaptogyrin binds lipids and helps to ensure that vesicles are uniformly sized, allowing for precise storage of neurotransmitters.

Cognitive impairment in Alzheimer’s disease is associated with Tau at the postsynapse. We show that multivalent Tau interactions arrest in vitro condensates and clusters mimicking the postsynaptic density that may result in synaptic dysfunction.

Proteins rich in phenylalanine-glycine (FG) repeats can phase separate through FG–FG interactions. The molecular interactions of an important FG-repeat protein, nucleoporin 98, have now been studied in liquid-like transient and amyloid-like cohesive states. These interactions underlie the behaviour of FG-repeat proteins and their function in physiological and pathological cell activities.

A solution NMR structure of the pre-mRNA retention and splicing (RES) core complex from budding yeast now reveals how the trimer stabilizes the RRM of its Snu17 subunit to promote pre-mRNA interactions within the spliceosome.

Alzheimer’s disease is characterized by the accumulation of aggregated tau protein. Here the authors find that Hsp chaperones, which normally protect cell homeostasis, can assemble with co-chaperones in a “multichaperone machinery” to target tau aggregation.

The authors present a method for the conversion of full-length tau protein into seeding-competent amyloid fibrils without heparin or other negatively charged co-factors, which could be useful for studying the effects of post-translational modifications on Tau aggregation as well as to identify potential inhibitors of tau aggregation. Biochemical experiments and solid-state NMR spectroscopy measurements show that these co-factor-free tau fibrils have similar properties as amyloid fibrils isolated from brain tissue but differ from those of commonly used heparin-induced tau fibrils.

The most frequent cause of familial Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are hexanucleotide repeat expansions in the non-coding region of the C9ORF72 gene that are translated into five dipeptide repeat (DPR) proteins. Here, the authors show that proline/arginine (PR) DPRs inhibit the prolyl isomerase PPIA and reveal the molecular mechanism of the impaired protein folding activity of PPIA by performing NMR measurements and determining a PR DPR bound PPIA crystal structure.

Cyclophilin A (CypA) is a peptidylprolyl isomerase that also has chaperone activity and interacts with the intrinsically disordered protein α-Synuclein (aSyn). Here, the authors combine NMR measurements and biochemical experiments to characterise the interplay between the catalysis of proline isomerization and molecular chaperone activity of CypA and find that both activities have opposing effects on aSyn and further show that the that cis/trans isomerization outpowers the holding activity of CypA.

Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are characterized by the pathological accumulation of α-synuclein. Here the authors employ fluorescent probes, electron microscopy and NMR spectroscopy to study the properties of α-synuclein aggregates that were amplified from patient brain extracts and observe a greater structural diversity among PD patients compared to MSA patients.

The SARS-CoV-2 viral genome is encapsulated by the nucleocapsid protein (N^SARS-CoV-2) that is essential for viral replication. Here, the authors show that RNA induces liquid-liquid phase separation of N^SARS-CoV-2 and how N^SARS-CoV-2 phosphorylation modulates RNA-binding and phase separation and that these RNA/N^SARS-CoV-2-droplets recruit and concentrate the SARS-CoV-2 RNA-dependent RNA polymerase complex in vitro, which would enable high initiation and elongation rates during viral transcription.

The condensation of RNA polymerase II (Pol II) into transcriptionally active clusters is critical for eukaryotic gene regulation and pre-mRNA transcription. Here the authors show that a tight network of tyrosine-proline interactions imparts temperature and concentration-dependent self-coacervation of Pol II’s C-terminal domain (CTD).

Protein aggregation plays a crucial role in several neurodegenerative diseases. Here the authors demonstrate that phosphorylation of β-amyloid aggregates—the pathological hallmark of Alzheimer's disease—can change the molecular properties of aggregates, suggesting how phosphorylation contributes to disease progression.

Small molecules that inhibit α-synuclein misfolding may have potential in the treatment of Parkinson’s disease. Fonseca-Ornelas et al.show that several of these molecules fail to block misfolding in the presence of membrane vesicles, and reveal how phtalocyanine tetrasulfonate, in contrast, overcomes this effect.

Tau aggregation, a hallmark of Alzheimer’s disease, disrupts neuron structure. Aging weakens chaperone defenses like Hsp90. This study designs β-Hsp90, a small peptide mimicking Hsp90, to prevent Tau aggregation, offering promise for new amyloid disease drugs.

Processing bodies (P-bodies) are non-membrane-bound protein/RNA granules in the cytosol. Here the authors combine bioinformatics, NMR and cell based assays and find that lysine is enriched in the disordered regions of P-body-associated proteins and show that lysine-rich polypeptides form highly dynamic lysine/RNA-coacervates and lysine acetylation reverses liquid-liquid phase separation.

The chaperone Hsp90 plays a key role in maintaining cellular homeostasis. Here the authors provide structural insights into substrate recognition and the pro-folding mechanism of Hsp90/co-chaperone complexes by studying the complex of Hsp90 with its co-chaperone FKBP51 and the substrate Tau bound Hsp90/FKBP51 ternary complex using a NMR based integrative approach.

The microtubule associated protein Tau also interacts with filamentous actin. Here the authors combine biophysical experiments and NMR studies to characterize the structural changes that occur in Tau upon binding to filamentous actin and show that phosphorylation of serine 262 attenuates actin binding of Tau.

NMR structures of the homodimeric repressor protein CylR2 collected from 25 °C to –16 °C provide glimpses of the molecular changes that occur during cold denaturation, yielding insights into protein folding and oligomerization.

Tau forms aggregates in the brains of Alzheimer patients. Here, the authors identify conditions, where the microtubule-binding repeats of Tau undergo a phosphorylation-dependent liquid–liquid phase separation, leading to molecular crowding in the formed Tau liquid droplets and characterize them by NMR and other biophysical methods.

The interaction of Hsp90 with misfolded monomeric transthyretin is characterized via biophysical approaches, and the data indicate that Hsp90 may have a distinct recognition mode for aggregation-prone proteins.

The realization that the cell is abundantly compartmentalized into biomolecular condensates has opened new opportunities for understanding the physics and chemistry underlying many cellular processes¹, fundamentally changing the study of biology². The term biomolecular condensate refers to non-stoichiometric assemblies that are composed of multiple types of macromolecules in cells, occur through phase transitions, and can be investigated by using concepts from soft matter physics³. As such, they are intimately related to aqueous two-phase systems⁴ and water-in-water emulsions⁵. Condensates possess tunable emergent properties such as interfaces, interfacial tension, viscoelasticity, network structure, dielectric permittivity, and sometimes interphase pH gradients and electric potentials^6–14. They can form spontaneously in response to specific cellular conditions or to active processes, and cells appear to have mechanisms to control their size and location^15–17. Importantly, in contrast to membrane-enclosed organelles such as mitochondria or peroxisomes, condensates do not require the presence of a surrounding membrane.

Aberrant liquid-to-gel transition of biological condensates can lead to pathological fibrillization and disease. Here, the authors demonstrate that a small molecule, methylene blue, can decouple gelation from fibrillization of tau liquid droplets.

Here, the authors show that pathogenic mutations in the polyalanine expansions of PHOX2B promote nascent structural conformations that trigger irreversible phase transitions that arrest wild-type PHOX2B, disrupting function.

α-Syn in CSF is a biomarker of neurodegenerative diseases; however, the detection of clinically relevant species is difficult. Here, the authors create a nanobody biosensor that reveals the presence of α-Syn in cells, which allow the detection of transmittable forms of α-Syn present in human CSF.

In this work, the authors identify Genipin as a small iridoid able to prevent alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage.

The effects of chaperones on the aggregation of different tau variants are examined in a large-scale study. Among other findings, the work reveals that DnaJA2 can inhibit tau aggregation, a role that is supported by analysis of samples from human brains.

Quaternary structure of α-synuclein fibrils characterized from human patients with Parkinson’s disease and Multiple System Atrophy modulates seeding in mouse primary oligodendroglial cultures.

Kulvicius et al. examine whether a multisensor system is better than single modality assessments for classifying infants’ fidgety movements using Convolutional Neural Network (CNN) architectures. A 3-sensor fusion performs significantly better than single modality for automated classification of infant motor patterns.