bims-proarb 2023-01-15 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2023–01–15
24 papers selected by
Rich Giadone, Harvard University

Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis.
G3BP1-dependent mechanism suppressing protein aggregation in Huntington's models and its demise upon stress granule assembly.
Mass spectrometric insights into protein aggregation.
TTR (transthyretin) leads the autophagy disaster relief team against TARDBP/TDP-43 proteinopathy.
Induced pluripotent stem cell-derived and directly reprogrammed neurons to study neurodegenerative diseases: The impact of aging signatures.
Fibril treatment changes protein interactions of tau and α-synuclein in human neurons.
Ready, steady, go: Rapid ribosomal scanning to reach start codons.
Epigenetic aging in adult neurogenesis.
Tau liquid-liquid phase separation is modulated by the Ca2+ -switched chaperone activity of the S100B protein.
Resveratrol alleviates inflammation and ER stress through SIRT1/NRF2 to delay ovarian aging in a short-lived fish.
ISSCR Education Committee syllabus and learning guide for enhancing stem cell literacy.
ERASing endoplasmic reticulum stress: the faster, the better.
Early Mitochondrial Defects in the 5xFAD Mouse Model of Alzheimer's Disease.
Autophagy genes in biology and disease.
Sensitive imaging of Endoplasmic reticulum (ER) autophagy with an acidity-reporting ER-Tracker.
HSP70-binding motifs function as protein quality control degrons.
A single-cell transcriptome atlas of glial diversity in the human hippocampus across the postnatal lifespan.
Cytosolic condensates rich in polyserine define subcellular sites of tau aggregation.
FDA approves second anti-amyloid antibody for Alzheimer disease.
Electrical signals in the ER are cell type and stimulus specific with extreme spatial compartmentalization in neurons.
Loss of epigenetic information as a cause of mammalian aging.
Distinct effects of SDC3 and FGFRL1 on selective neurodegeneration in AD and PD.
A three-dimensional spheroid co-culture system of neurons and astrocytes derived from Alzheimer's disease patients for drug efficacy testing.
Mitochondrial signalling and homeostasis: from cell biology to neurological disease.

Cell Chem Biol. 2022 Dec 31. pii: S2451-9456(22)00454-8. [Epub ahead of print]

Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis.

Shuhong Sun, Chao Wang, Pei Zhao, Gabe M Kline, Julia M D Grandjean, Xin Jiang, Richard Labaudiniere, R Luke Wiseman, Jeffery W Kelly, William E Balch.

  Genetic variation in alpha-1 antitrypsin (AAT) causes AAT deficiency (AATD) through liver aggregation-associated gain-of-toxic pathology and/or insufficient AAT activity in the lung manifesting as chronic obstructive pulmonary disease (COPD). Here, we utilize 71 AATD-associated variants as input through Gaussian process (GP)-based machine learning to study the correction of AAT folding and function at a residue-by-residue level by pharmacological activation of the ATF6 arm of the unfolded protein response (UPR). We show that ATF6 activators increase AAT neutrophil elastase (NE) inhibitory activity, while reducing polymer accumulation for the majority of AATD variants, including the prominent Z variant. GP-based profiling of the residue-by-residue response to ATF6 activators captures an unexpected role of the "gate" area in managing AAT-specific activity. Our work establishes a new spatial covariant (SCV) understanding of the convertible state of the protein fold in response to genetic perturbation and active environmental management by proteostasis enhancement for precision medicine.

Keywords:  Gaussian process; activating transcription factor 6 (ATF6); alpha-1 antitrypsin; alpha-1 antitrypsin deficiency; chaperones; genetic variation; machine learning; pharmacological ATF6 activators; precision medicine; protein aggregation; protein folding; protein misfolding disease; proteostasis; unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/j.chembiol.2022.12.004
Hum Mol Genet. 2023 Jan 05. pii: ddac304. [Epub ahead of print]

G3BP1-dependent mechanism suppressing protein aggregation in Huntington's models and its demise upon stress granule assembly.

Ricardo Gutiérrez-Garcia, Seda Koyuncu, Franziska Hommen, Saygın Bilican, Hyun Ju Lee, Azra Fatima, David Vilchez.

Stress granules are membrane-less ribonucleoprotein organelles that assemble upon exposure to stress conditions, but rapidly disassemble upon removal of stress. However, chronic stress can lead to persistent stress granules, a feature of distinct age-related neurodegenerative disorders. Among them, Huntington's disease (HD) which is caused by mutant expansion of the polyglutamine (polyQ) repeats of huntingtin protein (HTT), leading to its aggregation. To identify modulators of mutant HTT aggregation, we define its interactome in striatal neurons from patient-derived induced pluripotent stem cells (HD-iPSCs). We find that HTT interacts with G3BP1, a characteristic component of stress granules. Knockdown of G3BP1 increases mutant HTT protein levels and abolishes the ability of iPSCs as well as their differentiated neural counterparts to suppress mutant HTT aggregation. Moreover, loss of G3BP1 hastens polyQ-expanded aggregation and toxicity in the neurons of HD C. elegans models. Likewise, the assembly of G3BP1 into stress granules upon distinct stress conditions also reduces its interaction with HTT in human cells, promoting mutant HTT aggregation. Notably, enhancing the levels of G3BP1 is sufficient to induce proteasomal degradation of mutant HTT and prevent its aggregation, whereas the formation of stress granules blocks these ameliorative effects. In contrast, a mutant G3BP1 variant that cannot accumulate into granules retains its capacity to prevent mutant HTT aggregation even when the cells assemble stress granules. Thus, our findings indicate a direct role of G3BP1 and stress granule assembly in mutant HTT aggregation that may have implications for HD.

DOI: https://doi.org/10.1093/hmg/ddac304
Essays Biochem. 2023 Jan 13. pii: EBC20220103. [Epub ahead of print]

Mass spectrometric insights into protein aggregation.

Tara L Pukala.

  Protein aggregation is now recognized as a generic and significant component of the protein energy landscape. Occurring through a complex and dynamic pathway of structural interconversion, the assembly of misfolded proteins to form soluble oligomers and insoluble aggregates remains a challenging topic of study, both in vitro and in vivo. Since the etiology of numerous human diseases has been associated with protein aggregation, and it has become a field of increasing importance in the biopharmaceutical industry, the biophysical characterization of protein misfolded states and their aggregation mechanisms continues to receive increased attention. Mass spectrometry (MS) has firmly established itself as a powerful analytical tool capable of both detection and characterization of proteins at all levels of structure. Given inherent advantages of biological MS, including high sensitivity, rapid timescales of analysis, and the ability to distinguish individual components from complex mixtures with unrivalled specificity, it has found widespread use in the study of protein aggregation, importantly, where traditional structural biology approaches are often not amenable. The present review aims to provide a brief overview of selected MS-based approaches that can provide a range of biophysical descriptors associated with protein conformation and the aggregation pathway. Recent examples highlight where this technology has provided unique structural and mechanistic understanding of protein aggregation.

Keywords:  mass spectrometry; protein aggregation; protein structure

DOI:  https://doi.org/10.1042/EBC20220103
Autophagy. 2023 Jan 12.

TTR (transthyretin) leads the autophagy disaster relief team against TARDBP/TDP-43 proteinopathy.

Yuan-Ping Chu, Pei-Chuan Ho, Kuen-Jer Tsai.

  TTR (transthyretin) strikes a neuroprotective function in the prevention of amyloid-β (Aβ) deposition in Alzheimer disease (AD). Perturbation of the stringently controlled TARDBP/TDP-43 (TAR DNA binding protein) expression gives rise to cytoplasmic aggregation, characterized by TARDBP proteinopathy affiliated with several neurological disorders, including frontotemporal lobar degeneration with TARDBP pathology (FTLD-TDP) and amyotrophic lateral sclerosis/ALS. Proposedly, TTR can maintain cellular proteostasis susceptible to TARDBP aggregates and initiate its removal. Herein, we disclose that TTR upregulated in response to excessive TARDBP causes TARDBP aggregation in FTLD-TDP and co-accumulates with it. Moreover, TTR expression increases with age in FTLD-TDP but shows a downward decline in the elderly. TTR promotes macroautophagy/autophagy activity and facilitates aggregated TARDBP degradation via autophagy. Compellingly, TTR binds to ATF4 and boosts its nuclear import for autophagy upregulation. Therefore, TTR directs autophagy teamwork in bi-directional regulation through enhancing autophagy activity via ATF4 and chaperoning aggregated TARDBP to phagophores for degradation.

Keywords:  ATF4; FTLD; TDP-43; TTR; autophagy; proteinopathy

DOI:  https://doi.org/10.1080/15548627.2023.2167690
Front Aging Neurosci. 2022 ;14 1069482

Induced pluripotent stem cell-derived and directly reprogrammed neurons to study neurodegenerative diseases: The impact of aging signatures.

Simona Aversano, Carmen Caiazza, Massimiliano Caiazzo.

  Many diseases of the central nervous system are age-associated and do not directly result from genetic mutations. These include late-onset neurodegenerative diseases (NDDs), which represent a challenge for biomedical research and drug development due to the impossibility to access to viable human brain specimens. Advancements in reprogramming technologies have allowed to obtain neurons from induced pluripotent stem cells (iPSCs) or directly from somatic cells (iNs), leading to the generation of better models to understand the molecular mechanisms and design of new drugs. Nevertheless, iPSC technology faces some limitations due to reprogramming-associated cellular rejuvenation which resets the aging hallmarks of donor cells. Given the prominent role of aging for the development and manifestation of late-onset NDDs, this suggests that this approach is not the most suitable to accurately model age-related diseases. Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows the possibility to generate patient-derived neurons that maintain aging and epigenetic signatures of the donor. This aspect may be advantageous for investigating the role of aging in neurodegeneration and for finely dissecting underlying pathological mechanisms. Here, we will compare iPSC and iN models as regards the aging status and explore how this difference is reported to affect the phenotype of NDD in vitro models.

Keywords:  ALS; Alzheimer’s disease; Huntington’s disease; Parkinson’ disease; cell reprogramming; in vitro model

DOI:  https://doi.org/10.3389/fnagi.2022.1069482
J Biol Chem. 2023 Jan 09. pii: S0021-9258(23)00020-0. [Epub ahead of print] 102888

Fibril treatment changes protein interactions of tau and α-synuclein in human neurons.

Tagan A Griffin, Paul D Schnier, Elisa M Cleveland, Robert W Newberry, Julia Becker, George A Carlson.

  In several neurodegenerative disorders, the neuronal proteins tau and α-synuclein adopt aggregation-prone conformations capable of replicating within and between cells. To better understand how these conformational changes drive neuropathology, we compared the interactomes of tau and α-synuclein in the presence or absence of recombinant fibril seeds. Human embryonic stem cells with an inducible neurogenin-2 transgene were differentiated into glutamatergic neurons expressing 1) wild-type 0N4R tau, 2) mutant (P301L) 0N4R tau, 3) wild-type α-synuclein, or 4) mutant (A53T) α-synuclein, each genetically fused to a promiscuous biotin ligase (BioID2). Neurons expressing unfused BioID2 served as controls. After treatment with fibrils or PBS, interacting proteins were labelled with biotin in situ and quantified using mass spectrometry via tandem mass tag labelling. By comparing interactions in mutant versus wild-type neurons and in fibril- versus PBS-treated neurons, we observed changes in protein interactions that are likely relevant to disease progression. We identified forty-five shared interactors, suggesting that tau and α-synuclein function within some of the same pathways. Potential loci of shared interactions include microtubules, Wnt signaling complexes, and RNA granules. Following fibril treatment, physiological interactions decreased while other interactions, including those between tau and 14-3-3 η, increased. We confirmed that 14-3-3 proteins, which are known to colocalize with protein aggregates during neurodegeneration, can promote or inhibit tau aggregation in vitro depending on the specific combination of 14-3-3 isoform and tau sequence.

Keywords:  14-3-3; BioID; Interactome; Mass spectrometry; NGN2 neurons; Prion; Proteomics; Proximity biotinylation; Tau; α-Synuclein

DOI:  https://doi.org/10.1016/j.jbc.2023.102888
Mol Cell. 2023 Jan 05. pii: S1097-2765(22)01165-0. [Epub ahead of print]83(1): 9-11

Ready, steady, go: Rapid ribosomal scanning to reach start codons.

Helge Paternoga, Daniel N Wilson.

Wang et al. (2022)1 employ real-time single-molecule fluorescence spectroscopy to monitor eukaryotic translation initiation events, revealing that, while mRNA engagement by ribosomal 43S subunits is slow, the subsequent mRNA scanning process is rapid- ∼10 times faster than translation.

DOI: https://doi.org/10.1016/j.molcel.2022.12.008
Hippocampus. 2023 Jan 09.

Epigenetic aging in adult neurogenesis.

Sara Zocher, Tomohisa Toda.

  Neural stem cells (NSCs) in the hippocampus generate new neurons throughout life, which functionally contribute to cognitive flexibility and mood regulation. Yet adult hippocampal neurogenesis substantially declines with age and age-related impairments in NSC activity underlie this reduction. Particularly, increased NSC quiescence and consequently reduced NSC proliferation are considered to be major drivers of the low neurogenesis levels in the aged brain. Epigenetic regulators control the gene expression programs underlying NSC quiescence, proliferation and differentiation and are hence critical to the regulation of adult neurogenesis. Epigenetic alterations have also emerged as central hallmarks of aging, and recent studies suggest the deterioration of the NSC-specific epigenetic landscape as a driver of the age-dependent decline in adult neurogenesis. In this review, we summarize the recently accumulating evidence for a role of epigenetic dysregulation in NSC aging and propose perspectives for future research directions.

Keywords:  DNA methylation; Lamin B1; aging; chromatin; epigenetic; hippocampus; histone; neural stem cells; neurogenesis

DOI:  https://doi.org/10.1002/hipo.23494
J Neurochem. 2023 Jan 09.

Tau liquid-liquid phase separation is modulated by the Ca2+ -switched chaperone activity of the S100B protein.

Guilherme G Moreira, Cláudio M Gomes.

  Aggregation of the microtubule-associated protein tau is implicated in several neurodegenerative tauopathies including Alzheimer's disease (AD). Recent studies evidenced tau liquid-liquid phase separation (LLPS) into droplets as an early event in tau pathogenesis with the potential to enhance aggregation. Tauopathies like AD are accompanied by sustained neuroinflammation and the release of alarmins at early stages of inflammatory responses encompass protective functions. The Ca2+ -binding S100B protein is an alarmin augmented in AD that was recently implicated as a proteostasis regulator acting as a chaperone-type protein, inhibiting aggregation and toxicity through interactions of amyloidogenic clients with a regulatory surface exposed upon Ca2+ -binding. Here we expand the regulatory functions of S100B over protein condensation phenomena by reporting its Ca2+ -dependent activity as a modulator of tau LLPS induced by crowding agents (PEG) and metal ions (Zn2+ ). We observe that apo S100B has a negligible effect on PEG-induced tau demixing but that Ca2+ -bound S100B prevents demixing, resulting in a shift of the phase diagram boundary to higher crowding concentrations. Also, while incubation with apo S100B does not compromise tau LLPS, addition of Ca2+ results in a sharp decrease in turbidity, indicating that interactions with S100B-Ca2+ promote transition of tau to the mixed phase. Further, electrophoretic analysis and FLIM-FRET studies revealed that S100B incorporates into tau liquid droplets, suggesting an important stabilizing and chaperoning role contributing to minimize toxic tau aggregates. Resorting to Alexa488-labelled tau we observed that S100B-Ca2+ reduces the formation of tau fluorescent droplets, without compromising liquid-like behavior and droplet fusion events. The Zn2+ -binding properties of S100B also contribute to regulate Zn2+ -promoted tau LLPS as droplets are decreased by Zn2+ buffering by S100B, in addition to the Ca2+ -triggered interactions with tau. Altogether this work uncovers the versatility of S100B as a proteostasis regulator acting on protein condensation phenomena of relevance across the neurodegeneration continuum.

Keywords:  Molecular chaperone; S100 proteins; liquid droplets; protein aggregation; tauopathies

DOI:  https://doi.org/10.1111/jnc.15756
J Gerontol A Biol Sci Med Sci. 2023 Jan 11. pii: glad009. [Epub ahead of print]

Resveratrol alleviates inflammation and ER stress through SIRT1/NRF2 to delay ovarian aging in a short-lived fish.

Hongyan Zhu, Xiaowen Li, Mengxue Qiao, Xiaowen Sun, Guorong Li.

  Aging is a complex process in which the structure and function of various tissues and organs gradually decline with age, and ovarian aging affects the reproductive capacity of females and induces age-related diseases. Resveratrol, a natural polyphenol compound, extends the lifespan and has a protective effect on ovaries of vertebrates. However, the effects and underlying mechanisms of resveratrol delaying ovarian aging are unclear. In the present study, using an annual fish N. guentheri, we demonstrated that senescence-associated-beta-galactosidase (SA-β-gal) activity and lipofuscin accumulation increased with age in the ovaries, and resveratrol reversed this phenomenon. Resveratrol increased proliferating cell nuclear antigen (PCNA) expression and the oocyte proportions of primary growth stage, cortical alveolus stage and vitellogenesis stage, and decreased the number of atretic follicles in the ovaries of 6-, 9-, 12-month-old fish. Moreover, the expression of SIRT1 and NRF2 decreased and the levels of NF-κB, pro-inflammatory cytokines IL-1β, TNF-α and IL-8 and endoplasmic reticulum (ER) stress markers GRP78 and CHOP increased with aging, while resveratrol up-regulated SIRT1 and NRF2 expression and down-regulated NF-κB, IL-1β, TNF-α, IL-8, GRP78 and CHOP levels in the ovaries of 6-, 9-month-old fish. In HEK293T cells, knockdown SIRT1 decreased NRF2 and increased NF-κB p65, pro-inflammatory cytokines (IL-1β and TNF-α) and ER stress marker GRP78 expression markedly. Silencing SIRT1 and then treating the cells with resveratrol significantly reversed the phenomenon. Collectively, resveratrol might activate SIRT1/NRF2 to reduce inflammation and ER stress, and finally delay ovarian aging in a short-lived fish. This study highlights the protective effect and mechanism of resveratrol on ovarian aging.

Keywords:  SIRT1/NRF2; anti-aging; endoplasmic reticulum stress; inflammation; resveratrol

DOI:  https://doi.org/10.1093/gerona/glad009
Stem Cell Reports. 2022 Dec 27. pii: S2213-6711(22)00593-8. [Epub ahead of print]

ISSCR Education Committee syllabus and learning guide for enhancing stem cell literacy.

Julie R Perlin, William J Anderson, Sina Bartfeld, Anna Couturier, Yvanka de Soysa, R Scott Hawley, Ping Hu, Yuin-Han Loh, Lolitika Mandal, Zubin Master, Alysson R Muotri, Eugenia Piddini, Jose M Polo, Esteban O Mazzoni.

The rapidly evolving stem cell field puts much stress on developing educational resources. The ISSCR Education Committee has created a flexible stem cell syllabus rooted in core concepts to facilitate stem cell literacy. The free syllabus will be updated regularly to maintain accuracy and relevance.

DOI: https://doi.org/10.1016/j.stemcr.2022.12.004
Trends Cell Biol. 2023 Jan 07. pii: S0962-8924(22)00277-X. [Epub ahead of print]

ERASing endoplasmic reticulum stress: the faster, the better.

Jogender Singh.

  The endoplasmic reticulum (ER) has evolved multiple mechanisms to maintain homeostasis under stress conditions. A recent study by Efstathiou et al. identified a novel mechanism of silencing ER-associated RNAs by the exogenous RNA interference pathway. This adaptive response reduces protein flux in the ER under stressful conditions.

Keywords:  ERAD; RNA interference; RNA silencing; endoplasmic reticulum

DOI:  https://doi.org/10.1016/j.tcb.2022.12.003
J Alzheimers Dis. 2023 Jan 03.

Early Mitochondrial Defects in the 5xFAD Mouse Model of Alzheimer's Disease.

Neelam Sharma, Rupkatha Banerjee, Ronald L Davis.

   BACKGROUND: Mitochondrial (MT) dysfunction is a hallmark of Alzheimer's disease (AD). Amyloid-β protein precursor and amyloid-β peptides localize to MT and lead to MT dysfunction in familial forms of AD. This dysfunction may trigger subsequent types of pathology.
OBJECTIVE: To identify the MT phenotypes that occur early in order to help understand the cascade of AD pathophysiology.
METHODS: The 5xFAD mouse model was used to explore the time course of MT pathologies in both sexes. Protein biomarkers for MT dynamics were measured biochemically and MT function was measured using oxygen consumption and ATP assays.
RESULTS: We discovered progressive alterations in mitochondrial dynamics (biogenesis, fission, fusion, and mitophagy) and function (O2 consumption, ATP generation, and Ca2+ import) in the hippocampus of 5xFAD mice in both sexes as early as 2 months of age. Thus, mitochondrial dynamics and function become altered at young ages, consistent with an early role for mitochondria in the AD pathological cascade.
CONCLUSION: Our study offers the baseline information required to understand the hierarchical relationship between the multiple pathologies that develop in this mouse model and provides early biomarkers for MT dysfunction. This will aid in dissecting the temporal cascade of pathologies, understanding sex-specific differences, and in testing the efficacy of putative mitochondrial therapeutics.

Keywords:  Alzheimer’s disease; MT dysfunction; amyloid-β protein precursor; bioenergetics; biogenesis; fission/fusion; mitophagy

DOI:  https://doi.org/10.3233/JAD-220884
Nat Rev Genet. 2023 Jan 12.

Autophagy genes in biology and disease.

Hayashi Yamamoto, Sidi Zhang, Noboru Mizushima.

Macroautophagy and microautophagy are highly conserved eukaryotic cellular processes that degrade cytoplasmic material in lysosomes. Both pathways involve characteristic membrane dynamics regulated by autophagy-related proteins and other molecules, some of which are shared between the two pathways. Over the past few years, the application of new technologies, such as cryo-electron microscopy, coevolution-based structural prediction and in vitro reconstitution, has revealed the functions of individual autophagy gene products, especially in autophagy induction, membrane reorganization and cargo recognition. Concomitantly, mutations in autophagy genes have been linked to human disorders, particularly neurodegenerative diseases, emphasizing the potential pathogenic implications of autophagy defects. Accumulating genome data have also illuminated the evolution of autophagy genes within eukaryotes as well as their transition from possible ancestral elements in prokaryotes.

DOI: https://doi.org/10.1038/s41576-022-00562-w
Autophagy. 2023 Jan 12. 1-11

Sensitive imaging of Endoplasmic reticulum (ER) autophagy with an acidity-reporting ER-Tracker.

Yilong Shi, Xiaoxue Zou, Xianghui Zheng, Yimin Wu, Jiahuai Han, Shoufa Han.

  Macroautophagic/autophagic turnover of endoplasmic reticulum (reticulophagy) is critical for cell health. Herein we reported a sensitive fluorescence-on imaging of reticulophagy using a small molecule probe (ER-proRed) comprised of green-emissive fluorinated rhodol for ER targeting and nonfluorescent rhodamine-lactam prone to lysosome-triggered red fluorescence. Partitioned in ER to exhibit green fluorescence, ER-proRed gives intense red fluorescence upon co-delivery with ER into acidic lysosomes. Serving as the signal of reticulophagy, the turning on of red fluorescence enables discernment of reticulophagy induced by starvation, varied levels of reticulophagic receptors, and chemical agents such as etoposide and sodium butyrate. These results show ER probes optically activatable in lysosomes, such as ER-proRed, offer a sensitive and simplified tool for studying reticulophagy in biology and diseases.Abbreviations: Baf-A1, bafilomycin A1; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; CQ, chloroquine diphosphate; ER, endoplasmic reticulum; FHR, fluorinated hydrophobic rhodol; GFP, green fluorescent protein; Reticulophagy, selective autophagy of ER; RFP, red fluorescent protein; ROX, X-rhodamine; UPR, unfolded protein response.

Keywords:  Autophagy imaging; endoplasmic reticulum; fluorescence-on; lysosomal acidity; reticulophagy

DOI:  https://doi.org/10.1080/15548627.2023.2165759
Cell Mol Life Sci. 2023 Jan 07. 80(1): 32

HSP70-binding motifs function as protein quality control degrons.

Amanda B Abildgaard, Vasileios Voutsinos, Søren D Petersen, Fia B Larsen, Caroline Kampmeyer, Kristoffer E Johansson, Amelie Stein, Tommer Ravid, Claes Andréasson, Michael K Jensen, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen.

  Protein quality control (PQC) degrons are short protein segments that target misfolded proteins for proteasomal degradation, and thus protect cells against the accumulation of potentially toxic non-native proteins. Studies have shown that PQC degrons are hydrophobic and rarely contain negatively charged residues, features which are shared with chaperone-binding regions. Here we explore the notion that chaperone-binding regions may function as PQC degrons. When directly tested, we found that a canonical Hsp70-binding motif (the APPY peptide) functioned as a dose-dependent PQC degron both in yeast and in human cells. In yeast, Hsp70, Hsp110, Fes1, and the E3 Ubr1 target the APPY degron. Screening revealed that the sequence space within the chaperone-binding region of APPY that is compatible with degron function is vast. We find that the number of exposed Hsp70-binding sites in the yeast proteome correlates with a reduced protein abundance and half-life. Our results suggest that when protein folding fails, chaperone-binding sites may operate as PQC degrons, and that the sequence properties leading to PQC-linked degradation therefore overlap with those of chaperone binding.

Keywords:  Chaperone; Proteasome; Protein degradation; Protein quality control; Protein stability; Protein unfolding

DOI:  https://doi.org/10.1007/s00018-022-04679-3
Cell Stem Cell. 2023 Jan 05. pii: S1934-5909(22)00491-X. [Epub ahead of print]30(1): 113

A single-cell transcriptome atlas of glial diversity in the human hippocampus across the postnatal lifespan.

Yijing Su, Yi Zhou, Mariko L Bennett, Shiying Li, Marc Carceles-Cordon, Lu Lu, Sooyoung Huh, Dennisse Jimenez-Cyrus, Benjamin C Kennedy, Sudha K Kessler, Angela N Viaene, Ingo Helbig, Xiaosong Gu, Joel E Kleinman, Thomas M Hyde, Daniel R Weinberger, David W Nauen, Hongjun Song, Guo-Li Ming.

DOI: https://doi.org/10.1016/j.stem.2022.12.007
Proc Natl Acad Sci U S A. 2023 Jan 17. 120(3): e2217759120

Cytosolic condensates rich in polyserine define subcellular sites of tau aggregation.

Evan Lester, Meaghan Van Alstyne, Kathleen L McCann, Spoorthy Reddy, Li Yi Cheng, Jeff Kuo, James Pratt, Roy Parker.

  Tau aggregates are a hallmark of multiple neurodegenerative diseases and can contain RNAs and RNA-binding proteins, including serine/arginine repetitive matrix protein 2 (SRRM2) and pinin (PNN). However, how these nuclear proteins mislocalize and their influence on the prion-like propagation of tau aggregates is unknown. We demonstrate that polyserine repeats in SRRM2 and PNN are necessary and sufficient for recruitment to tau aggregates. Moreover, we show tau aggregates preferentially grow in association with endogenous cytoplasmic assemblies-mitotic interchromatin granules and cytoplasmic speckles (CSs)-which contain SRRM2 and PNN. Polyserine overexpression in cells nucleates assemblies that are sites of tau aggregate growth. Further, modulating the levels of polyserine-containing proteins results in a corresponding change in tau aggregation. These findings define a specific protein motif, and cellular condensates, that promote tau aggregate propagation. As CSs form in induced pluripotent stem cell (iPSC) derived neurons under inflammatory or hyperosmolar stress, they may affect tau aggregate propagation in neurodegenerative disease.

Keywords:  Alzheimer’s disease; RNA-binding proteins; SRRM2; frontotemporal dementia; tau

DOI:  https://doi.org/10.1073/pnas.2217759120
Nat Rev Drug Discov. 2023 Jan 09.

FDA approves second anti-amyloid antibody for Alzheimer disease.

Asher Mullard.

DOI: https://doi.org/10.1038/d41573-023-00004-0
Cell Rep. 2023 Jan 05. pii: S2211-1247(22)01844-7. [Epub ahead of print]42(1): 111943

Electrical signals in the ER are cell type and stimulus specific with extreme spatial compartmentalization in neurons.

Evan P Campbell, Ahmed A Abushawish, Lauren A Valdez, Miriam K Bell, Melita Haryono, Padmini Rangamani, Brenda L Bloodgood.

  The endoplasmic reticulum (ER) is a tortuous organelle that spans throughout a cell with a continuous membrane containing ion channels, pumps, and transporters. It is unclear if stimuli that gate ER ion channels trigger substantial membrane potential fluctuations and if those fluctuations spread beyond their site of origin. Here, we visualize ER membrane potential dynamics in HEK cells and cultured rat hippocampal neurons by targeting a genetically encoded voltage indicator specifically to the ER membrane. We report the existence of clear cell-type- and stimulus-specific ER membrane potential fluctuations. In neurons, direct stimulation of ER ryanodine receptors generates depolarizations that scale linearly with stimulus strength and reach tens of millivolts. However, ER potentials do not spread beyond the site of receptor activation, exhibiting steep attenuation that is exacerbated by intracellular large conductance K+ channels. Thus, segments of ER can generate large depolarizations that are actively restricted from impacting nearby, contiguous membrane.

Keywords:  BK channels; CP: Cell biology; CP: Neuroscience; ER; HEK cells; dendrites; electrical compartmentalization; genetically encoded voltage sensor; membrane potential; neurons

DOI:  https://doi.org/10.1016/j.celrep.2022.111943
Cell. 2023 Jan 09. pii: S0092-8674(22)01570-7. [Epub ahead of print]

Loss of epigenetic information as a cause of mammalian aging.

Jae-Hyun Yang, Motoshi Hayano, Patrick T Griffin, João A Amorim, Michael S Bonkowski, John K Apostolides, Elias L Salfati, Marco Blanchette, Elizabeth M Munding, Mital Bhakta, Yap Ching Chew, Wei Guo, Xiaojing Yang, Sun Maybury-Lewis, Xiao Tian, Jaime M Ross, Giuseppe Coppotelli, Margarita V Meer, Ryan Rogers-Hammond, Daniel L Vera, Yuancheng Ryan Lu, Jeffrey W Pippin, Michael L Creswell, Zhixun Dou, Caiyue Xu, Sarah J Mitchell, Abhirup Das, Brendan L O'Connell, Sachin Thakur, Alice E Kane, Qiao Su, Yasuaki Mohri, Emi K Nishimura, Laura Schaevitz, Neha Garg, Ana-Maria Balta, Meghan A Rego, Meredith Gregory-Ksander, Tatjana C Jakobs, Lei Zhong, Hiroko Wakimoto, Jihad El Andari, Dirk Grimm, Raul Mostoslavsky, Amy J Wagers, Kazuo Tsubota, Stephen J Bonasera, Carlos M Palmeira, Jonathan G Seidman, Christine E Seidman, Norman S Wolf, Jill A Kreiling, John M Sedivy, George F Murphy, Richard E Green, Benjamin A Garcia, Shelley L Berger, Philipp Oberdoerffer, Stuart J Shankland, Vadim N Gladyshev, Bruce R Ksander, Andreas R Pfenning, Luis A Rajman, David A Sinclair.

  All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.

Keywords:  DNA damage; RCM; aging; chromatin; epigenetic clock; epigenetic reprogramming; relocalization of chromatin modifier; senescence

DOI:  https://doi.org/10.1016/j.cell.2022.12.027
FASEB J. 2023 Feb;37(2): e22773

Distinct effects of SDC3 and FGFRL1 on selective neurodegeneration in AD and PD.

Juelu Wang, Peiye Chen, Bolang Hu, Fang Cai, Qin Xu, Sipei Pan, Yili Wu, Weihong Song.

  Alzheimer's disease (AD) and Parkinson's disease (PD) are age-dependent neurodegenerative disorders. There is a profound neuronal loss in the basal forebrain cholinergic system in AD and severe dopaminergic deficiency within the nigrostriatal pathway in PD. Swedish APP (APPSWE ) and SNCAA53T mutations promote Aβ generation and α-synuclein aggregation, respectively, and have been linked to the pathogenesis of AD and PD. However, the mechanisms underlying selective cholinergic and dopaminergic neurodegeneration in AD and PD are still unknown. We demonstrated that APPSWE mutation enhanced Aβ generation and increased cell susceptibility to Aβ oligomer in cholinergic SN56 cells, whereas SNCAA53T mutations promoted aggregates formation and potentiated mutant α-synuclein oligomer-induced cytotoxicity in MN9D cells. Furthermore, syndecan-3 (SDC3) and fibroblast growth factor receptor-like 1 (FGFRL1) genes were differentially expressed in SN56 and MN9D cells carrying APPSWE or SNCAA53T mutation. SDC3 and FGFRL1 proteins were preferentially expressed in the cholinergic nucleus and dopaminergic neurons of APPSWE and SNCAA53T mouse models, respectively. Finally, the knockdown of SDC3 and FGFRL1 attenuated oxidative stress-induced cell death in SN56-APPSWE and MN9D-SNCAA53T cells. The results demonstrate that SDC3 and FGFRL1 mediated the specific effects of APPSWE and SNCAA53T on cholinergic and dopaminergic neurodegeneration in AD and PD, respectively. Our study suggests that SDC3 and FGFRL1 could be potential targets to alleviate the selective neurodegeneration in AD and PD.

Keywords:  Alzheimer's disease; Parkinson's disease; fibroblast growth factor receptor-like 1; neurodegeneration; syndecan-3

DOI:  https://doi.org/10.1096/fj.202201359R
Cell Prolif. 2023 Jan 11. e13399

A three-dimensional spheroid co-culture system of neurons and astrocytes derived from Alzheimer's disease patients for drug efficacy testing.

HyunJung Park, Jaehyeon Kim, Chongsuk Ryou.

Cell culture systems derived from the progenitor cells of human patients have many advantages over animal models for therapeutic drug testing and studies of disease pathogenesis. Here we describe a three-dimensional (3D) spheroid co-culture system of neurons and astrocytes derived from induced pluripotent stem cells-neural precursor cells (iPSCs-NPCs) of Alzheimer's disease (AD) patients or healthy individuals that can provide information on drug efficacy unobtainable by 2D co-culture or monoculture approaches. iPSCs-NPCs of healthy controls or AD patients were seeded onto 96-well U-bottom plates and incubated with neuronal differentiation medium for one week and with astrocytic medium for two weeks to replicate the temporal order of cell maturation during brain development. These 3D spheroid models expressed marker proteins for mature neurons and astrocytes. In particular, patient-derived spheroids showed beta-amyloid (Aβ) accumulation as revealed by thioflavin T (ThT) staining and ELISA. Aggregation of Aβ induced caspase activation and cell death, while the neuroprotectants nordihydroguaiaretic acid (NDGA) and curcumin (CU) reduced the levels of both ThT and caspase staining. Taken together, these results demonstrate the feasibility of our 3D spheroids combined with ThT and caspase staining as a patient-based anti-AD drug screening platform.

DOI: https://doi.org/10.1111/cpr.13399
Trends Neurosci. 2023 Jan 10. pii: S0166-2236(22)00239-9. [Epub ahead of print]

Mitochondrial signalling and homeostasis: from cell biology to neurological disease.

Jack J Collier, Monika Oláhová, Thomas G McWilliams, Robert W Taylor.

  Efforts to understand how mitochondrial dysfunction contributes to neurodegeneration have primarily focussed on the role of mitochondria in neuronal energy metabolism. However, progress in understanding the etiological nature of emerging mitochondrial functions has yielded new ideas about the mitochondrial basis of neurological disease. Studies aimed at deciphering how mitochondria signal through interorganellar contacts, vesicular trafficking, and metabolic transmission have revealed that mitochondrial regulation of immunometabolism, cell death, organelle dynamics, and neuroimmune interplay are critical determinants of neural health. Moreover, the homeostatic mechanisms that exist to protect mitochondrial health through turnover via nanoscale proteostasis and lysosomal degradation have become integrated within mitochondrial signalling pathways to support metabolic plasticity and stress responses in the nervous system. This review highlights how these distinct mitochondrial pathways converge to influence neurological health and contribute to disease pathology.

Keywords:  immunity; inflammation; metabolism; mitochondrial-derived vesicles; mitochondria–lysosome axis; quality control

DOI:  https://doi.org/10.1016/j.tins.2022.12.001