bims-proned 2024-05-26 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024–05–26
twelve papers selected by
Verena Kohler, Umeå University

Post-translational Modification of α-Synuclein Modifies Monomer Dynamics and Aggregation Kinetics.
Broad proteomics analysis of seeding-induced aggregation of α-synuclein in M83 neurons reveals remodeling of proteostasis mechanisms that might contribute to Parkinson's disease pathogenesis.
Nuclear aggregates of NONO/SFPQ and A-to-I-edited RNA in Parkinson's disease and dementia with Lewy bodies.
Understanding genetic risks: Computational exploration of human β-Synuclein nsSNPs and their potential impact on structural alteration.
Insights into Calpain Activation and Rho-ROCK Signaling in Parkinson's Disease and Aging.
Usp14 deficiency removes α-synuclein by regulating S100A8/A9 in Parkinson's disease.
Novel 4-triazole phenyl amide (4-TPA) molecules: Potent promoters of α-synuclein fibril disassembly.
The autophagy-lysosome pathway: a potential target in the chemical and gene therapeutic strategies for Parkinson's disease.
Toxicity of the model protein 3×GFP arises from degradation overload, not from aggregate formation.
Strategies for measuring concentrations and forms of amyloid-β peptides.
3-Hydroxyanthranilic Acid Delays Paralysis in Caenorhabditis elegans Models of Amyloid-Beta and Polyglutamine Proteotoxicity.
Red emissive fluorescent carbon dots based on ternary carbon source for imaging α-synuclein fibrils.

bioRxiv. 2024 May 09. pii: 2024.05.06.592473. [Epub ahead of print]

Post-translational Modification of α-Synuclein Modifies Monomer Dynamics and Aggregation Kinetics.

Kasun Gamage, Binyou Wang, Eldon R Hard, Thong Van, Ana Galesic, George R Phillips, Matthew Pratt, Lisa J Lapidus.

The intrinsically disordered protein α-Synuclein is identified as a major toxic aggregate in Parkinson's as well as several other neurodegenerative diseases. Recent work on this protein has focused on the effects of posttranslational modifications on aggregation kinetics. Among these, O-GlcNAcylation of α-Synuclein has been observed to inhibit the aggregation propensity of the protein. Here we investigate the monomer dynamics of two O-GlcNAcylated α-Synucleins, α-Syn(gT72) and α-Syn(gS87) and correlate them with the aggregation kinetics. We find that, compared to the unmodified protein, glycosylation at T72 makes the protein less compact and more diffusive while glycosylation at S87 makes the protein more compact and less diffusive. Based on a model of the earliest steps in aggregation, we predict that T72 should aggregate slower than unmodified protein, which is confirmed by ThT fluorescence measurements. In contrast, S87 should aggregate faster, which is not mirrored in ThT kinetics of later fibril formation but does not rule out a higher rate of formation of small oligomers. Together, these results show that posttranslational modifications do not uniformly affect aggregation propensity.

DOI: https://doi.org/10.1101/2024.05.06.592473
Mol Brain. 2024 May 22. 17(1): 26

Broad proteomics analysis of seeding-induced aggregation of α-synuclein in M83 neurons reveals remodeling of proteostasis mechanisms that might contribute to Parkinson's disease pathogenesis.

Casey J Lumpkin, Hiral Patel, Gregory K Potts, Shilpi Chaurasia, Lauren Gibilisco, Gyan P Srivastava, Janice Y Lee, Nathan J Brown, Patricia Amarante, Jon D Williams, Eric Karran, Matthew Townsend, Dori Woods, Brinda Ravikumar.

  Aggregation of misfolded α-synuclein (α-syn) is a key characteristic feature of Parkinson's disease (PD) and related synucleinopathies. The nature of these aggregates and their contribution to cellular dysfunction is still not clearly elucidated. We employed mass spectrometry-based total and phospho-proteomics to characterize the underlying molecular and biological changes due to α-syn aggregation using the M83 mouse primary neuronal model of PD. We identified gross changes in the proteome that coincided with the formation of large Lewy body-like α-syn aggregates in these neurons. We used protein-protein interaction (PPI)-based network analysis to identify key protein clusters modulating specific biological pathways that may be dysregulated and identified several mechanisms that regulate protein homeostasis (proteostasis). The observed changes in the proteome may include both homeostatic compensation and dysregulation due to α-syn aggregation and a greater understanding of both processes and their role in α-syn-related proteostasis may lead to improved therapeutic options for patients with PD and related disorders.

Keywords:  M83 mouse model; Parkinson’s disease; Total and phospho proteomics

DOI:  https://doi.org/10.1186/s13041-024-01099-1
Neuron. 2024 May 16. pii: S0896-6273(24)00328-3. [Epub ahead of print]

Nuclear aggregates of NONO/SFPQ and A-to-I-edited RNA in Parkinson's disease and dementia with Lewy bodies.

Nandkishore R Belur, Bernabe I Bustos, Steven J Lubbe, Joseph R Mazzulli.

  Neurodegenerative diseases are commonly classified as proteinopathies that are defined by the aggregation of a specific protein. Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are classified as synucleinopathies since α-synuclein (α-syn)-containing inclusions histopathologically define these diseases. Unbiased biochemical analysis of PD and DLB patient material unexpectedly revealed novel pathological inclusions in the nucleus comprising adenosine-to-inosine (A-to-I)-edited mRNAs and NONO and SFPQ proteins. These inclusions showed no colocalization with Lewy bodies and accumulated at levels comparable to α-syn. NONO and SFPQ aggregates reduced the expression of the editing inhibitor ADAR3, increasing A-to-I editing mainly within human-specific, Alu-repeat regions of axon, synaptic, and mitochondrial transcripts. Inosine-containing transcripts aberrantly accumulated in the nucleus, bound tighter to recombinant purified SFPQ in vitro, and potentiated SFPQ aggregation in human dopamine neurons, resulting in a self-propagating pathological state. Our data offer new insight into the inclusion composition and pathophysiology of PD and DLB.

Keywords:  Lewy bodies; RNA binding proteins; RNA editing; iPSC models; inverted Alu repeats; neurodegeneration; nuclear retention; protein aggregation; synucleinopathies

DOI:  https://doi.org/10.1016/j.neuron.2024.05.003
Neurosci Lett. 2024 May 18. pii: S0304-3940(24)00204-0. [Epub ahead of print] 137826

Understanding genetic risks: Computational exploration of human β-Synuclein nsSNPs and their potential impact on structural alteration.

Pragati Mahur, Abhishek Sharma, Gulnaz Jahan, S G Adithya, Amit Kumar Singh, Jayaraman Muthukumaran, Monika Jain.

  Synucleins are pivotal in neurodegenerative conditions. Beta-synuclein (β-synuclein) is part of the synuclein protein family alongside alpha-synuclein (α-synuclein) and gamma-synuclein (γ-synuclein). These proteins, found mainly in brain tissue and cancers, are soluble and unstructured. β-synuclein shares significant similarity with α-synuclein, especially in their N-terminus, with a 90% match. However, their aggregation tendencies differ significantly. While α-synuclein aggregation is believed to be counteracted by β-synuclein, which occurs in conditions like Parkinson's disease, β-synuclein may counteract α-synuclein's toxic effects on the nervous system, offering potential treatment for neurodegenerative diseases. Under normal circumstances, β-synuclein may guard against disease by interacting with α-synuclein. Yet, in pathological environments with heightened levels or toxic substances, it might contribute to disease. Our research aims to explore potential harmful mutations in the β-synuclein using computational tools to predict their destabilizing impact on protein structure. Consensus analysis revealed rs1207608813 (A63P), rs1340051870 (S72F), and rs1581178262 (G36C) as deleterious. These findings highlight the intricate relationship between nsSNPs and protein function, shedding light on their potential implications in disease pathways. Understanding the structural consequences of nsSNPs is crucial for elucidating their role in pathogenesis and developing targeted therapeutic interventions. Our results offer a robust computational framework for identifying neurodegenerative disorder-related mutations from SNP datasets, potentially reducing the costs associated with experimental characterization.

Keywords:  Molecular Dynamics; Neurodegenerative disorders; Parkinson’s disease; SNCB; nsSNPs; β-synuclein

DOI:  https://doi.org/10.1016/j.neulet.2024.137826
Biomedicines. 2024 May 13. pii: 1074. [Epub ahead of print]12(5):

Insights into Calpain Activation and Rho-ROCK Signaling in Parkinson's Disease and Aging.

Amy Gathings, Vandana Zaman, Narendra L Banik, Azizul Haque.

  Parkinson's disease (PD), a progressive neurodegenerative disease, has no cure, and current therapies are not effective at halting disease progression. The disease affects mid-brain dopaminergic neurons and, subsequently, the spinal cord, contributing to many debilitating symptoms associated with PD. The GTP-binding protein, Rho, plays a significant role in the cellular pathology of PD. The downstream effector of Rho, Rho-associated kinase (ROCK), plays multiple functions, including microglial activation and induction of inflammatory responses. Activated microglia have been implicated in the pathology of many neurodegenerative diseases, including PD, that initiate inflammatory responses, leading to neuron death. Calpain expression and activity is increased following glial activation, which triggers the Rho-ROCK pathway and induces inflammatory T cell activation and migration as well as mediates toxic α-synuclein (α-syn) aggregation and neuron death, indicating a pivotal role for calpain in the inflammatory and degenerative processes in PD. Increased calpain activity and Rho-ROCK activation may represent a new mechanism for increased oxidative damage in aging. This review will summarize calpain activation and the role of the Rho-ROCK pathway in oxidative stress and α-syn aggregation, their influence on the neurodegenerative process in PD and aging, and possible strategies and research directions for therapeutic intervention.

Keywords:  Parkinson’s disease; Rho-ROCK; aging; calpain; neurodegeneration; α-synuclein

DOI:  https://doi.org/10.3390/biomedicines12051074
Cell Mol Life Sci. 2024 May 23. 81(1): 232

Usp14 deficiency removes α-synuclein by regulating S100A8/A9 in Parkinson's disease.

Liuyan Ding, Lin Lu, Shaohui Zheng, Zhiling Zhang, Xingting Huang, Runfang Ma, Mengran Zhang, Zongtang Xu, Minshan Chen, Zhimei Guo, Si Zhu, Junwei Gong, Hengxu Mao, Wenlong Zhang, Pingyi Xu.

  Ubiquitin-proteasome system dysfunction triggers α-synuclein aggregation, a hallmark of neurodegenerative diseases, such as Parkinson's disease (PD). However, the crosstalk between deubiquitinating enzyme (DUBs) and α-synuclein pathology remains unclear. In this study, we observed a decrease in the level of ubiquitin-specific protease 14 (USP14), a DUB, in the cerebrospinal fluid (CSF) of PD patients, particularly females. Moreover, CSF USP14 exhibited a dual correlation with α-synuclein in male and female PD patients. To investigate the impact of USP14 deficiency, we crossed USP14 heterozygous mouse (USP14+/-) with transgenic A53T PD mouse (A53T-Tg) or injected adeno-associated virus (AAV) carrying human α-synuclein (AAV-hα-Syn) in USP14+/- mice. We found that Usp14 deficiency improved the behavioral abnormities and pathological α-synuclein deposition in female A53T-Tg or AAV-hα-Syn mice. Additionally, Usp14 inactivation attenuates the pro-inflammatory response in female AAV-hα-Syn mice, whereas Usp14 inactivation demonstrated opposite effects in male AAV-hα-Syn mice. Mechanistically, the heterodimeric protein S100A8/A9 may be the downstream target of Usp14 deficiency in female mouse models of α-synucleinopathies. Furthermore, upregulated S100A8/A9 was responsible for α-synuclein degradation by autophagy and the suppression of the pro-inflammatory response in microglia after Usp14 knockdown. Consequently, our study suggests that USP14 could serve as a novel therapeutic target in PD.

Keywords:  Autophagy; Parkinson’s disease; S100A8/A9; USP14; α-synuclein

DOI:  https://doi.org/10.1007/s00018-024-05246-8
Eur J Med Chem. 2024 May 16. pii: S0223-5234(24)00370-2. [Epub ahead of print]273 116490

Novel 4-triazole phenyl amide (4-TPA) molecules: Potent promoters of α-synuclein fibril disassembly.

Chenyang Qiu, Ruonan Wei, Jiang Bian, Xin Lin, Tengfei Bai, Jie He, Xiaomin Guo, Yong Chu.

  Parkinson's disease profoundly compromises patients' daily lives, and the disassembly of α-synuclein aggregates, a primary pathological factor, represents a promising therapeutic approach. In this study, we conducted a systematic screening and optimization process to identify the novel scaffold B37, a 4-triazolyl-phenylamine derivative, exhibiting a potent disassembly activity of 1.1 μM against α-synuclein preformed fibrils. Notably, B37 demonstrated significant neuroprotective effects, ameliorated autophagic dysfunction induced by preformed fibrils, mitigated oxidative stress, and restored the co-localization of preformed fibrils with lysosomes. Transmission electron microscopy corroborated its in vitro disassembly function. Pharmacokinetic profiling revealed favorable parameters with a receptible blood-brain barrier permeability. B37 emerges as a promising lead compound for further optimization, aiming to develop a highly effective agent targeting the disassembly of α-synuclein aggregates to treat neurodegenerative diseases like Parkinson's disease.

Keywords:  4-triazole phenyl amide; Morphology; Parkinson's disease; α-synuclein fibril depolymerizer

DOI:  https://doi.org/10.1016/j.ejmech.2024.116490
Neural Regen Res. 2025 Jan 01. 20(1): 139-158

The autophagy-lysosome pathway: a potential target in the chemical and gene therapeutic strategies for Parkinson's disease.

Fengjuan Jiao, Lingyan Meng, Kang Du, Xuezhi Li.

Parkinson's disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such as α-synuclein in neurons. As one of the major intracellular degradation pathways, the autophagy-lysosome pathway plays an important role in eliminating these proteins. Accumulating evidence has shown that upregulation of the autophagy-lysosome pathway may contribute to the clearance of α-synuclein aggregates and protect against degeneration of dopaminergic neurons in Parkinson's disease. Moreover, multiple genes associated with the pathogenesis of Parkinson's disease are intimately linked to alterations in the autophagy-lysosome pathway. Thus, this pathway appears to be a promising therapeutic target for treatment of Parkinson's disease. In this review, we briefly introduce the machinery of autophagy. Then, we provide a description of the effects of Parkinson's disease-related genes on the autophagy-lysosome pathway. Finally, we highlight the potential chemical and genetic therapeutic strategies targeting the autophagy-lysosome pathway and their applications in Parkinson's disease.

DOI: https://doi.org/10.4103/NRR.NRR-D-23-01195
J Cell Sci. 2024 May 20. pii: jcs.261977. [Epub ahead of print]

Toxicity of the model protein 3×GFP arises from degradation overload, not from aggregate formation.

Shotaro Namba, Hisao Moriya.

  While protein aggregation can cause cytotoxicity, it also forms to mitigate cytotoxicity from misfolded proteins, though the nature of these contrasting aggregates remains unclear. We previously found that overproduction (op) of a three green fluorescent protein linked protein (3×GFP) induces giant aggregates, and is detrimental to growth. Here, we investigated the mechanism of growth inhibition by 3×GFP-op using non-aggregative 3×MOX-op as a control. The 3×GFP aggregates were induced by misfolding, and 3×GFP-op had higher cytotoxicity than 3×MOX-op because it perturbs the ubiquitin-proteasome system. Static aggregates formed by 3×GFP-op dynamically trapped Hsp70, causing the heat shock response. Systematic analysis of mutants deficient in the protein quality control suggested that 3×GFP-op did not cause critical Hsp70 depletion and aggregation functioned in the direction of mitigating toxicity. Artificial trapping of essential cell cycle regulators into 3×GFP aggregates caused abnormalities in the cell cycle. In conclusion, the formation of the giant 3×GFP aggregates itself is not cytotoxic, as it does not entrap and deplete essential proteins. Rather, it is productive, inducing the heat shock response while preventing an overload to the degradation system.

Keywords:  Aggregation; Fluorocent protein; Hsp70; Overproduction; Toxicity; Yeast

DOI:  https://doi.org/10.1242/jcs.261977
Biosens Bioelectron. 2024 May 18. pii: S0956-5663(24)00410-X. [Epub ahead of print]259 116405

Strategies for measuring concentrations and forms of amyloid-β peptides.

Hangyu Shen, Keyin Liu, Fangong Kong, Mingguang Ren, Xiaoying Wang, Shoujuan Wang.

  Alzheimer's disease (AD) is affecting more and more people worldwide without the effective treatment, while the existed pathological mechanism has been confirmed barely useful in the treatment. Amyloid-β peptide (Aβ), a main component of senile plaque, is regarded as the most promising target in AD treatment. Aβ clearance from AD brain seems to be a reliably therapeutic strategy, as the two exited drugs, GV-971 and aducanumab, are both developed based on it. However, doubt still exists. To exhaustive expound on the pathological mechanism of Aβ, rigorous analyses on the concentrations and aggregation forms are essential. Thus, it is attracting broad attention these years. However, most of the sensors have not been used in pathological studies, as the lack of the bridge between analytical chemist and pathologists. In this review, we made a brief introduce on Aβ-related pathological mechanism included in β-amyloid hypothesis to elucidate the detection conditions of sensor methods. Furthermore, a summary of the sensor methods was made, which were based on Aβ concentrations and form detections that have been developed in the past 10 years. As the greatest number of the sensors were built on fluorescent spectroscopy, electrochemistry, and Roman spectroscopy, detailed elucidation on them was made. Notably, the aggregation process is another important factor in revealing the progress of AD and developing the treatment methods, so the sensors on monitoring Aβ aggregation processes were also summarized.

Keywords:  Aggregation form; Alzheimer's disease; Amyloid-β; Concentration

DOI:  https://doi.org/10.1016/j.bios.2024.116405
Biomolecules. 2024 May 18. pii: 599. [Epub ahead of print]14(5):

3-Hydroxyanthranilic Acid Delays Paralysis in Caenorhabditis elegans Models of Amyloid-Beta and Polyglutamine Proteotoxicity.

Bradford T Hull, Kayla M Miller, Caroline Corban, Grant Backer, Susan Sheehan, Ron Korstanje, George L Sutphin.

  Age is the primary risk factor for neurodegenerative diseases such as Alzheimer's and Huntington's disease. Alzheimer's disease is the most common form of dementia and a leading cause of death in the elderly population of the United States. No effective treatments for these diseases currently exist. Identifying effective treatments for Alzheimer's, Huntington's, and other neurodegenerative diseases is a major current focus of national scientific resources, and there is a critical need for novel therapeutic strategies. Here, we investigate the potential for targeting the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3HAA) using Caenorhabditis elegans expressing amyloid-beta or a polyglutamine peptide in body wall muscle, modeling the proteotoxicity in Alzheimer's and Huntington's disease, respectively. We show that knocking down the enzyme that degrades 3HAA, 3HAA dioxygenase (HAAO), delays the age-associated paralysis in both models. This effect on paralysis was independent of the protein aggregation in the polyglutamine model. We also show that the mechanism of protection against proteotoxicity from HAAO knockdown is mimicked by 3HAA supplementation, supporting elevated 3HAA as the mediating event linking HAAO knockdown to delayed paralysis. This work demonstrates the potential for 3HAA as a targeted therapeutic in neurodegenerative disease, though the mechanism is yet to be explored.

Keywords:  Alzheimer’s disease; Caenorhabditis elegans; Huntington’s disease; kynurenine; metabolism; neurodegeneration; proteotoxicity; tryptophan

DOI:  https://doi.org/10.3390/biom14050599
J Colloid Interface Sci. 2024 May 18. pii: S0021-9797(24)01108-1. [Epub ahead of print]670 576-584

Red emissive fluorescent carbon dots based on ternary carbon source for imaging α-synuclein fibrils.

Jintao Zhang, Wan-Chun Luo, Yu Zhang, Xi Li, Ming Jiang, Kun Huang, Xu Yu, Li Xu.

  The misfolding and aggregation of α-synuclein monomers usually cause the occurrence and development of Parkinson's disease (PD). It is important to develop effective methods for detection of α-synuclein aggregates. Carbon dots (CDs) could be the potential fluorescence probe for this purpose owing to their appreciated optical properties. However, undefined structure of CDs and complicated three-dimensional structure of protein severely hindered the design of fluorescence probe towards protein aggregates. Herein, a red emissive fluorescent amphiphilic CD, named as CL-9, was designed with a high sensitivity to α-synuclein fibrils by a one-step heating process, using the ternary carbon source, including Congo red, l-tryptophan and urea. The CL-9 exhibited turn-on red emissive fluorescence towards α-synuclein fibril, but remained no change towards its monomer. Compared with the original Congo red dye, CL-9 exhibited stronger turn-on red fluorescence towards α-synuclein fibrils with better anti-photobleaching resistance, biocompatibility and signal-to-noise ratio. The CL-9 was successful as a fluorescent probe to image α-synuclein fibrils in NL-5901 C. elegans. The present study provided a feasible approach using the multiple carbon sources to construct the CDs based fluorescence probe targeting amyloid proteins.

Keywords:  Amyloid protein aggregation; Carbon dots; Congo red; Fluorescence probe; Parkinson’s disease; α-synuclein

DOI:  https://doi.org/10.1016/j.jcis.2024.05.129