bims-proned 2023-09-03 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2023–09–03
nine papers selected by
Verena Kohler, University of Graz

Gut mucosal cells transfer α-synuclein to the vagus nerve.
The yeast guanine nucleotide exchange factor Sec7 is a bottleneck in spatial protein quality control and detoxifies neurological disease proteins.
The emerging role of ATP as a cosolute for biomolecular processes.
Proteolytically Stable Diaza-Peptide Foldamers Mimic Helical Hot Spots of Protein-Protein Interactions and Act as Natural Chaperones.
Amyloid pathology reduces ELP3 expression and tRNA modifications leading to impaired proteostasis.
Chaotic aging: intrinsically disordered proteins in aging-related processes.
Inflammasome assembly in neurodegenerative diseases.
Synergistic Screening of Peptide-Based Biotechnological Drug Candidates for Neurodegenerative Diseases Using Yeast Display and Phage Display.
Activation of transient receptor potential vanilloid 1 ameliorates tau accumulation-induced synaptic damage and cognitive dysfunction via autophagy enhancement.

bioRxiv. 2023 Aug 14. pii: 2023.08.14.553305. [Epub ahead of print]

Gut mucosal cells transfer α-synuclein to the vagus nerve.

Rashmi Chandra, Arpine Sokratian, Katherine R Chavez, Stephanie King, Sandip M Swain, Joshua C Snyder, Andrew B West, Rodger A Liddle.

Epidemiological and histopathological findings have raised the possibility that misfolded α-synuclein protein might spread from the gut to the brain and increase the risk of Parkinson's disease (PD). While past experimental studies in mouse models have relied on gut injections of exogenous recombinant α-synuclein fibrils to study gut to brain α-synuclein transfer, the possible origins of misfolded α-synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of the gut mucosa express α-synuclein. In this study, we employed mouse intestinal organoids expressing human α-synuclein to observe the transfer of α-synuclein protein from gut epithelial cells in organoids co-cultured with vagal nodose neurons that are otherwise devoid of α-synuclein expression. In intact mice that express pathological human α-synuclein, but no mouse α-synuclein, α-synuclein fibril templating activity emerges in α-synuclein seeded fibril aggregation assays in tissues from the gut, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human α-synuclein expression to intestinal epithelial cells, α-synuclein fibril-templating activity transfers to the vagus nerve and to the dorsal motor nucleus. Subdiaphragmatic vagotomy prior to the induction of α-synuclein expression in the gut epithelial cells effectively protects the hindbrain from the emergence of α-synuclein fibril templating activity. Overall, these findings highlight a novel potential non-neuronal source of fibrillar α-synuclein protein that might arise in gut mucosal cells.

DOI: https://doi.org/10.1101/2023.08.14.553305
Sci Rep. 2023 08 28. 13(1): 14068

The yeast guanine nucleotide exchange factor Sec7 is a bottleneck in spatial protein quality control and detoxifies neurological disease proteins.

Roja Babazadeh, Kara L Schneider, Arthur Fischbach, Xinxin Hao, Beidong Liu, Thomas Nystrom.

ER-to-Golgi trafficking partakes in the sorting of misfolded cytoplasmic proteins to reduce their cytological toxicity. We show here that yeast Sec7, a protein involved in proliferation of the Golgi, is part of this pathway and participates in an Hsp70-dependent formation of insoluble protein deposits (IPOD). Sec7 associates with the disaggregase Hsp104 during a mild heat shock and increases the rate of Hsp104 diffusion in an Hsp70-dependent manner when overproduced. Sec7 overproduction increased formation of IPODs from smaller aggregates and mitigated the toxicity of Huntingtin exon-1 upon heat stress while Sec7 depletion increased sensitivity to aẞ42 of the Alzheimer's disease and α-synuclein of the Parkinson's disease, suggesting a role of Sec7 in mitigating proteotoxicity.

DOI: https://doi.org/10.1038/s41598-023-41188-0
Biol Chem. 2023 Sep 04.

The emerging role of ATP as a cosolute for biomolecular processes.

Alexander Hautke, Simon Ebbinghaus.

  ATP is an important small molecule that appears at outstandingly high concentration within the cellular medium. Apart from its use as a source of energy and a metabolite, there is increasing evidence for important functions as a cosolute for biomolecular processes. Owned to its solubilizing kosmotropic triphosphate and hydrophobic adenine moieties, ATP is a versatile cosolute that can interact with biomolecules in various ways. We here use three models to categorize these interactions and apply them to review recent studies. We focus on the impact of ATP on biomolecular solubility, folding stability and phase transitions. This leads us to possible implications and therapeutic interventions in neurodegenerative diseases.

Keywords:  ATP; cosolute; hydrotrope; neurodegenerative diseases; phase transitions; protein aggregation

DOI:  https://doi.org/10.1515/hsz-2023-0202
J Med Chem. 2023 Aug 26.

Proteolytically Stable Diaza-Peptide Foldamers Mimic Helical Hot Spots of Protein-Protein Interactions and Act as Natural Chaperones.

Chenghui Shi, Julia Kaffy, Tâp Ha-Duong, Jean-François Gallard, Alain Pruvost, Aloise Mabondzo, Lidia Ciccone, Sandrine Ongeri, Nicolo Tonali.

A novel class of peptidomimetic foldamers based on diaza-peptide units are reported. Circular dichroism, attenuated total reflection -Fourier transform infrared, NMR, and molecular dynamics studies demonstrate that unlike the natural parent nonapeptide, the specific incorporation of one diaza-peptide unit at the N-terminus allows helical folding in water, which is further reinforced by the introduction of a second unit at the C-terminus. The ability of these foldamers to resist proteolysis, to mimic the small helical hot spot of transthyretin-amyloid β (Aβ) cross-interaction, and to decrease pathological Aβ aggregation demonstrates that the introduction of diaza-peptide units is a valid approach for designing mimics or inhibitors of protein-protein interaction and other therapeutic peptidomimetics. This study also reveals that small peptide foldamers can play the same role as physiological chaperone proteins and opens a new way to design inhibitors of amyloid protein aggregation, a hallmark of more than 20 serious human diseases such as Alzheimer's disease.

DOI: https://doi.org/10.1021/acs.jmedchem.3c00611
Biochim Biophys Acta Mol Basis Dis. 2023 Aug 26. pii: S0925-4439(23)00223-5. [Epub ahead of print] 166857

Amyloid pathology reduces ELP3 expression and tRNA modifications leading to impaired proteostasis.

Marisa Pereira, Diana R Ribeiro, Maximilian Berg, Andy P Tsai, Chuanpeng Dong, Kwangsik Nho, Stefanie Kaiser, Miguel Moutinho, Ana R Soares.

  Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by accumulation of β-amyloid aggregates and loss of proteostasis. Transfer RNA (tRNA) modifications play a crucial role in maintaining proteostasis, but their impact in AD remains unclear. Here, we report that expression of the tRNA modifying enzyme ELP3 is reduced in the brain of AD patients and amyloid mouse models and negatively correlates with amyloid plaque mean density. We further show that SH-SY5Y neuronal cells carrying the amyloidogenic Swedish familial AD mutation (SH-SWE) display reduced ELP3 levels, tRNA hypomodifications and proteostasis impairments when compared to cells not carrying the mutation (SH-WT). Additionally, exposing SH-WT cells to the secretome of SH-SWE cells led to reduced ELP3 expression, wobble uridine tRNA hypomodification, and increased protein aggregation. Importantly, correcting tRNA deficits due to ELP3 reduction reverted proteostasis impairments. These findings suggest that amyloid pathology dysregulates proteostasis by reducing ELP3 expression and tRNA modification levels, and that targeting tRNA modifications may be a potential therapeutic avenue to restore neuronal proteostasis in AD and preserve neuronal function.

Keywords:  Alzheimer's disease; Elongator complex subunit 3 (ELP3); Proteostasis; Translation; tRNA modifications

DOI:  https://doi.org/10.1016/j.bbadis.2023.166857
Cell Mol Life Sci. 2023 Aug 27. 80(9): 269

Chaotic aging: intrinsically disordered proteins in aging-related processes.

Vladimir D Manyilov, Nikolay S Ilyinsky, Semen V Nesterov, Baraa M G A Saqr, Guy W Dayhoff, Egor V Zinovev, Simon S Matrenok, Alexander V Fonin, Irina M Kuznetsova, Konstantin K Turoverov, Valentin Ivanovich, Vladimir N Uversky.

  The development of aging is associated with the disruption of key cellular processes manifested as well-established hallmarks of aging. Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) have no stable tertiary structure that provide them a power to be configurable hubs in signaling cascades and regulate many processes, potentially including those related to aging. There is a need to clarify the roles of IDPs/IDRs in aging. The dataset of 1702 aging-related proteins was collected from established aging databases and experimental studies. There is a noticeable presence of IDPs/IDRs, accounting for about 36% of the aging-related dataset, which is however less than the disorder content of the whole human proteome (about 40%). A Gene Ontology analysis of the used here aging proteome reveals an abundance of IDPs/IDRs in one-third of aging-associated processes, especially in genome regulation. Signaling pathways associated with aging also contain IDPs/IDRs on different hierarchical levels, revealing the importance of "structure-function continuum" in aging. Protein-protein interaction network analysis showed that IDPs present in different clusters associated with different aging hallmarks. Protein cluster with IDPs enrichment has simultaneously high liquid-liquid phase separation (LLPS) probability, "nuclear" localization and DNA-associated functions, related to aging hallmarks: genomic instability, telomere attrition, epigenetic alterations, and stem cells exhaustion. Intrinsic disorder, LLPS, and aggregation propensity should be considered as features that could be markers of pathogenic proteins. Overall, our analyses indicate that IDPs/IDRs play significant roles in aging-associated processes, particularly in the regulation of DNA functioning. IDP aggregation, which can lead to loss of function and toxicity, could be critically harmful to the cell. A structure-based analysis of aging and the identification of proteins that are particularly susceptible to disturbances can enhance our understanding of the molecular mechanisms of aging and open up new avenues for slowing it down.

Keywords:  Aggregation; Aging; Epigenetics; Intrinsic disorder; Liquid–liquid phase separation; Protein function; Protein structure; Protein–protein interaction; Proteomics; Proteostasis

DOI:  https://doi.org/10.1007/s00018-023-04897-3
Trends Neurosci. 2023 Aug 24. pii: S0166-2236(23)00174-1. [Epub ahead of print]

Inflammasome assembly in neurodegenerative diseases.

Jagjit Singh, Maria L Habean, Nikhil Panicker.

  Neurodegenerative disorders are characterized by the progressive dysfunction and death of selectively vulnerable neuronal populations, often associated with the accumulation of aggregated host proteins. Sustained brain inflammation and hyperactivation of inflammasome complexes have been increasingly demonstrated to contribute to neurodegenerative disease progression. Here, we review molecular mechanisms leading to inflammasome assembly in neurodegeneration. We focus primarily on four degenerative brain disorders in which inflammasome hyperactivation has been well documented: Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and the spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We discuss shared and divergent principles of inflammasome assembly across these disorders, and underscore the differences between neurodegeneration-associated inflammasome activation pathways and their peripheral-immune counterparts. We examine how aberrant assembly of inflammasome complexes may amplify pathology in neurodegeneration, including misfolded protein aggregation, and highlight prospects for neurotherapeutic interventions based on targeting inflammasome pathways.

Keywords:  AIM2; Alzheimer’s disease; NLRC4; NLRP1; NLRP3; Parkinson’s disease; amyotrophic lateral sclerosis; frontotemporal dementia; multiple sclerosis

DOI:  https://doi.org/10.1016/j.tins.2023.07.009
ACS Chem Neurosci. 2023 Aug 28.

Synergistic Screening of Peptide-Based Biotechnological Drug Candidates for Neurodegenerative Diseases Using Yeast Display and Phage Display.

Cemile Elif Özçelik, Özge Beğli, Ahmet Hınçer, Recep Erdem Ahan, Mehmet Seçkin Kesici, Oğuzhan Oğuz, Talip Serkan Kasırga, Salih Özçubukçu, Urartu Özgür Şafak Şeker.

  Peptide therapeutics are robust and promising molecules for treating diverse disease conditions. These molecules can be developed from naturally occurring or mimicking native peptides, through rational design and peptide libraries. We developed a new platform for the rapid screening of the peptide therapeutics for disease targets. In the course of the study, we aimed to employ our platform to screen a new generation of peptide therapeutic candidates against aggregation-prone protein targets. Two peptide drug candidates were screened for protein aggregation-prone diseases, namely, Parkinson's and Alzheimer's diseases. Currently, there are several therapeutic applications that are only effective in masking or slowing down symptom development. Nonetheless, different approaches are being developed for inhibiting amyloid aggregation in the secondary nucleation phase, which is critical for amyloid fibril formation. Instead of targeting secondary nucleated protein structures, we tried to inhibit the aggregation of monomeric amyloid units as a novel approach for halting the disease condition. To achieve this, we combined yeast surface display and phage display library platforms. We expressed α-synuclein, amyloid β40, and amyloid β42 on the yeast surface, and we selected peptides by using phage display library. After iterative biopanning cycles optimized for yeast cells, several peptides were selected for interaction studies. All of the peptides have been used for in vitro characterization methods, which are quartz crystal microbalance-dissipation (QCM-D) measurement, atomic force microscopy (AFM) imaging, dot-blotting, and ThT assay, and some of them have yielded promising results in blocking fibrillization. The rest of the peptides, although, interacted with amyloid units which made them usable as a sensor molecule candidate. Therefore, peptides selected by yeast surface display and phage display library combination are good choice for diverse disease-prone molecule inhibition, particularly those inhibiting fibrillization. Additionally, these selected peptides can be used as drugs and sensors to detect diseases quickly and halt disease progression.

Keywords:  neurodegenerative disease; peptide-based drug discovery; phage display library; yeast surface display

DOI:  https://doi.org/10.1021/acschemneuro.3c00248
CNS Neurosci Ther. 2023 Aug 29.

Activation of transient receptor potential vanilloid 1 ameliorates tau accumulation-induced synaptic damage and cognitive dysfunction via autophagy enhancement.

Tao Zhang, Yuan Tian, Xiaoqing Zheng, Ruomeng Li, Li Hu, Xindong Shui, Yingxue Mei, Quling Wang, Mi Zhang, Xiuzhi Zheng, Long Wang, Dongmei Chen, Wucheng Tao, Tae Ho Lee.

   AIMS: The autophagy-lysosomal pathway is important for maintaining cellular proteostasis, while dysfunction of this pathway has been suggested to drive the aberrant intraneuronal accumulation of tau protein, leading to synaptic damage and cognitive impairment. Previous studies have demonstrated that the activation of transient receptor potential vanilloid 1 (TRPV1) by capsaicin has a positive impact on cognition and AD-related biomarkers. However, the effect and mechanism of TPRV1 activation on neuronal tau homeostasis remain elusive.
METHODS: A mouse model of tauopathy was established by overexpressing full-length human tau in the CA3 area. Mice were fed capsaicin diet (0.0125%) or normal diet for 9 weeks. The cognitive ability, synaptic function, tau phosphorylation levels, and autophagy markers were detected. In vitro, capsaicin-induced alterations in cellular autophagy and tau degradation were characterized using two cell models. Besides, various inhibitors were applied to validate the role of TRPV1-mediated autophagy enhancement in tau clearance.
RESULTS: We observed that TRPV1 activation by capsaicin effectively mitigates hippocampal tau accumulation-induced synaptic damages, gliosis, and cognitive impairment in vivo. Capsaicin promotes the degradation of abnormally accumulated tau through enhancing autophagic function in neurons, which is dependent on TRPV1-mediated activation of AMP-activated protein kinase (AMPK) and subsequent inhibition of the mammalian target of rapamycin (mTOR). Blocking AMPK activation abolishes capsaicin-induced autophagy enhancement and tau degradation in neurons.
CONCLUSION: Our findings reveal that capsaicin-induced TRPV1 activation confers neuroprotection by restoring neuronal tau homeostasis via modulating cellular autophagy and provides additional evidence to support the potential of TRPV1 as a therapeutic target for tauopathies.

Keywords:  autophagy; capsaicin; cognition; tau; tauopathy; transient receptor potential vanilloid 1

DOI:  https://doi.org/10.1111/cns.14432