bims-proned 2024-01-28 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024–01–28
twenty-one papers selected by
Verena Kohler, Umeå University

The disordered protein SERF promotes α-Synuclein aggregation through liquid-liquid phase separation.
From Synaptic Physiology to Synaptic Pathology: The Enigma of α-Synuclein.
Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.
Updates on Aβ Processing by Hsp90, BRICHOS, and Newly Reported Distinctive Chaperones.
Misfolded alpha-synuclein in amyotrophic lateral sclerosis: Implications for diagnosis and treatment.
ALS' Perfect Storm: C9orf72-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis.
Glial senescence enhances α-synuclein pathology owing to its insufficient clearance caused by autophagy dysfunction.
Computational insights into the cross-talk between medin and Aβ: implications for age-related vascular risk factors in Alzheimer's disease.
Constitutive Endolysosomal Perforation in Neurons allows Induction of α-Synuclein Aggregation by Internalized Pre-Formed Fibrils.
Using Generative Modeling to Endow with Potency Initially Inert Compounds with Good Bioavailability and Low Toxicity.
The Multifaceted Role of Cofilin in Neurodegeneration and Stroke: Insights into Pathogenesis and Targeting as a Therapy.
Current Technologies Unraveling the Significance of Post-Translational Modifications (PTMs) as Crucial Players in Neurodegeneration.
The 75-99 C-Terminal Peptide of URG7 Protein Promotes α-Synuclein Disaggregation.
α-Synuclein reduces acetylserotonin O-methyltransferase mediated melatonin biosynthesis by microtubule-associated protein 1 light chain 3 beta-related degradation pathway.
Mitochondrial CISD1/Cisd accumulation blocks mitophagy and genetic or pharmacological inhibition rescues neurodegenerative phenotypes in Pink1/parkin models.
Acupuncture Activates IRE1/XBP1 Endoplasmic Reticulum Stress Pathway in Parkinson's Disease Model Rats.
Cooperative dissolution of peptidomimetic vesicles and amyloid β fibrils.
PAD2 dysregulation and aberrant protein citrullination feature prominently in reactive astrogliosis and myelin protein aggregation in sporadic ALS.
Mutations in Tau Protein Promote Aggregation by Favoring Extended Conformations.
Network Analysis Performed on Transcriptomes of Parkinson's Disease Patients Reveals Dysfunction in Protein Translation.
Wild-Type DCTN1 Suppresses the Aggregation of DCTN1 Mutants Associated with Perry Disease.

J Biol Chem. 2024 Jan 23. pii: S0021-9258(24)00043-7. [Epub ahead of print] 105667

The disordered protein SERF promotes α-Synuclein aggregation through liquid-liquid phase separation.

He-Ning Liu, Ting Wang, Jin-Jian Hu, Long Chen, Xiangyan Shi, Yan-Mei Li, Shi-Zhong Luo.

  The aggregation of α-Synuclein (α-Syn) into amyloid fibrils is the hallmark of Parkinson's disease (PD). Under stress or other pathological conditions, the accumulation of α-Syn oligomers is the main contributor to the cytotoxicity. A potential approach for treating PD involves preventing the accumulation of these α-Syn oligomers. In this study, we present a novel mechanism involving a conserved group of disorderly proteins known as small EDRK rich factor (SERF), which promotes the aggregation of α-Syn through a co-phase separation process. Using diverse methods like confocal microscopy, fluorescence recovery after photobleaching assays, Solution-state NMR spectroscopy and western-blot, we determined that the N-terminal domain of SERF plays a role in the interactions that occur during co-phase separation. Within these droplets, α-Syn undergoes a gradual transformation from solid condensates to amyloid fibrils, while SERF is excluded from the condensates and dissolves into the solution. Notably, in vivo experiments show that SERF co-phase separation with α-Syn significantly reduces the deposition of α-Syn oligomers and decreases its cellular toxicity under stress. These findings suggest that SERF accelerates the conversion of α-Syn from highly toxic oligomers to less toxic fibrils through co-phase separation, thereby mitigating the biological damage of α-Syn aggregation.

Keywords:  SERF; aggregation; co-phase separation; oligomer toxicity; α-Synuclein

DOI:  https://doi.org/10.1016/j.jbc.2024.105667
Int J Mol Sci. 2024 Jan 12. pii: 986. [Epub ahead of print]25(2):

From Synaptic Physiology to Synaptic Pathology: The Enigma of α-Synuclein.

Kaja Nordengen, Cecilie Morland.

  Alpha-synuclein (α-syn) has gained significant attention due to its involvement in neurodegenerative diseases, particularly Parkinson's disease. However, its normal function in the human brain is equally fascinating. The α-syn protein is highly dynamic and can adapt to various conformational stages, which differ in their interaction with synaptic elements, their propensity to drive pathological aggregation, and their toxicity. This review will delve into the multifaceted role of α-syn in different types of synapses, shedding light on contributions to neurotransmission and overall brain function. We describe the physiological role of α-syn at central synapses, including the bidirectional interaction between α-syn and neurotransmitter systems.

Keywords:  GABA; acetylcholine; dopamine; glutamate; norepinephrine; serotonin; synapse; synuclein

DOI:  https://doi.org/10.3390/ijms25020986
Mol Neurodegener. 2024 Jan 22. 19(1): 8

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.

Bilal Khalil, Miriam Linsenmeier, Courtney L Smith, James Shorter, Wilfried Rossoll.

  Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery. Recent advances suggest that beyond their canonical role in the nuclear import of protein cargoes, nuclear-import receptors (NIRs) can prevent and reverse aberrant phase transitions of TDP-43, FUS, and related prion-like RBPs and restore their nuclear localization and function. Here, we showcase the NIR family and how they recognize cargo, drive nuclear import, and chaperone prion-like RBPs linked to ALS/FTD. We also discuss the promise of enhancing NIR levels and developing potentiated NIR variants as therapeutic strategies for ALS/FTD and related neurodegenerative proteinopathies.

Keywords:  Aberrant phase transition; Amyotrophic lateral sclerosis; Chaperone; FUS; Frontotemporal dementia; Importin; Nuclear pore; Nucleocytoplasmic transport; Protein aggregation; RNA-binding proteins; TDP-43

DOI:  https://doi.org/10.1186/s13024-023-00698-1
Biomolecules. 2023 Dec 22. pii: 16. [Epub ahead of print]14(1):

Updates on Aβ Processing by Hsp90, BRICHOS, and Newly Reported Distinctive Chaperones.

Mohammed Iqbal, Shea-Lorane Lewis, Shivani Padhye, Umesh Kumar Jinwal.

  Alzheimer's disease (AD) is an extremely devastating neurodegenerative disease, and there is no cure for it. AD is specified as the misfolding and aggregation of amyloid-β protein (Aβ) and abnormalities in hyperphosphorylated tau protein. Current approaches to treat Alzheimer's disease have had some success in slowing down the disease's progression. However, attempts to find a cure have been largely unsuccessful, most likely due to the complexity associated with AD pathogenesis. Hence, a shift in focus to better understand the molecular mechanism of Aβ processing and to consider alternative options such as chaperone proteins seems promising. Chaperone proteins act as molecular caretakers to facilitate cellular homeostasis under standard conditions. Chaperone proteins like heat shock proteins (Hsps) serve a pivotal role in correctly folding amyloid peptides, inhibiting mitochondrial dysfunction, and peptide aggregation. For instance, Hsp90 plays a significant role in maintaining cellular homeostasis through its protein folding mechanisms. In this review, we analyze the most recent studies from 2020 to 2023 and provide updates on Aβ regulation by Hsp90, BRICHOS domain chaperone, and distinctive newly reported chaperones.

Keywords:  Alzheimer’s disease; BRICHOS domain chaperone; Hsp90; amyloid-β protein; artificial chaperone; chemical chaperone; engineerable chaperone

DOI:  https://doi.org/10.3390/biom14010016
Eur J Neurol. 2024 Jan 25. e16206

Misfolded alpha-synuclein in amyotrophic lateral sclerosis: Implications for diagnosis and treatment.

Richard Smith, Hanna Hovren, Robert Bowser, Nadine Bakkar, Ralph Garruto, Albert Ludolph, John Ravits, Lia Gaertner, Davan Murphy, Russ Lebovitz.

   BACKGROUND: Alpha-synuclein (α-Syn) oligomers and fibrils have been shown to augment the aggregation of TAR DNA-binding Protein 43 (TDP-43) monomers in vitro, supporting the idea that TDP-43 proteinopathies such as ALS may be modulated by the presence of toxic forms of α-Syn 1. Recently, parkinsonian features were reported in a study of European patients 2 and Lewy bodies have been demonstrated pathologically in a similar series of patients 3. Based on these and other considerations, we sought to determine whether seed-competent α-Syn can be identified in spinal fluid of patients with ALS including familial, sporadic, and Guamanian forms of the disease.
METHODS: Based on the finding that α-Syn has been found to be a prion-like protein, we have utilized a validated α-Synuclein seed amplification assay to determine if seed-competent α-Syn could be detected in the spinal fluid of patients with ALS.
RESULTS: Toxic species of α-Syn were detected in CSF in 18 of 127 ALS patients, 5 of whom were from Guam. Two out of twenty six samples from patients with C9orf72 variant ALS had positive seed-amplification assay (SAAs). No positive tests were noted in superoxide dismutase type 1 ALS subjects (n = 14). The SAA was negative in 31 control subjects.
CONCLUSIONS: Our findings suggest that a sub-group of ALS occurs in which self-replicating α-Syn is detectable and likely contributes to its pathogenesis. This finding may have implications for the diagnosis and treatment of this disorder.

Keywords:  alpha-synuclein; amyotrophic lateral sclerosis; neurodegeneration; seed amplification assay; self-replicating proteins

DOI:  https://doi.org/10.1111/ene.16206
Cells. 2024 Jan 17. pii: 178. [Epub ahead of print]13(2):

ALS' Perfect Storm: C9orf72-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis.

Paulien H Smeele, Giuliana Cesare, Thomas Vaccari.

  Protein homeostasis is essential for neuron longevity, requiring a balanced regulation between protein synthesis and degradation. The clearance of misfolded and aggregated proteins, mediated by autophagy and the ubiquitin-proteasome systems, maintains protein homeostasis in neurons, which are post-mitotic and thus cannot use cell division to diminish the burden of misfolded proteins. When protein clearance pathways are overwhelmed or otherwise disrupted, the accumulation of misfolded or aggregated proteins can lead to the activation of ER stress and the formation of stress granules, which predominantly attempt to restore the homeostasis by suppressing global protein translation. Alterations in these processes have been widely reported among studies investigating the toxic function of dipeptide repeats (DPRs) produced by G4C2 expansion in the C9orf72 gene of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this review, we outline the modalities of DPR-induced disruptions in protein homeostasis observed in a wide range of models of C9orf72-linked ALS/FTD. We also discuss the relative importance of each DPR for toxicity, possible synergies between DPRs, and discuss the possible functional relevance of DPR aggregation to disease pathogenesis. Finally, we highlight the interdependencies of the observed effects and reflect on the importance of feedback and feedforward mechanisms in their contribution to disease progression. A better understanding of DPR-associated disease pathogenesis discussed in this review might shed light on disease vulnerabilities that may be amenable with therapeutic interventions.

Keywords:  ALS; C9orf72; ER stress; FTD; autophagy; dipeptide repeats; lysosome; proteasome; protein homeostasis

DOI:  https://doi.org/10.3390/cells13020178
Cell Death Discov. 2024 Jan 26. 10(1): 50

Glial senescence enhances α-synuclein pathology owing to its insufficient clearance caused by autophagy dysfunction.

Bin Hong, Yosuke Ohtake, Takahide Itokazu, Toshihide Yamashita.

Parkinson's disease (PD) is characterized by the pathological accumulation of α-synuclein (α-syn) and loss of dopaminergic neurons in the substantia nigra. Aging is a significant risk factor for PD. The accumulation of senescent glial cells in the aged brain contributes to PD progression by inducing chronic neuroinflammatory processes. However, although the insufficient degradation of α-syn aggregates results in PD deterioration, the possible alteration in the ability of α-syn clearance in senescent glia has received little attention. In this study, we investigated how aging and glial senescence affect the capacity of α-syn clearance. We found that following the intra-striatal injection of human α-syn (hu-α-syn) preformed fibril, hu-α-syn pathology persisted more in aged mice compared with younger mice and that aged microglia exhibited greater accumulation of hu-α-syn than younger microglia. Moreover, in vitro assay revealed that the clearance of hu-α-syn was primarily dependent on the autophagy-lysosome system rather than on the ubiquitin-proteasome system and that the capacity of hu-α-syn clearance was diminished in senescent glia because of autophagy-lysosome system dysfunction. Overall, this study provides new insights into the role of senescent glia in PD pathogenesis.

DOI: https://doi.org/10.1038/s41420-024-01816-8
Brief Bioinform. 2024 Jan 22. pii: bbad526. [Epub ahead of print]25(2):

Computational insights into the cross-talk between medin and Aβ: implications for age-related vascular risk factors in Alzheimer's disease.

Fengjuan Huang, Xinjie Fan, Ying Wang, Yu Zou, Jiangfang Lian, Chuang Wang, Feng Ding, Yunxiang Sun.

  The aggregation of medin forming aortic medial amyloid is linked to arterial wall degeneration and cerebrovascular dysfunction. Elevated levels of arteriolar medin are correlated with an increased presence of vascular amyloid-β (Aβ) aggregates, a hallmark of Alzheimer's disease (AD) and vascular dementia. The cross-interaction between medin and Aβ results in the formation of heterologous fibrils through co-aggregation and cross-seeding processes both in vitro and in vivo. However, a comprehensive molecular understanding of the cross-interaction between medin and Aβ-two intrinsically disordered proteins-is critically lacking. Here, we employed atomistic discrete molecular dynamics simulations to systematically investigate the self-association, co-aggregation and also the phenomenon of cross-seeding between these two proteins. Our results demonstrated that both Aβ and medin were aggregation prone and their mixture tended to form β-sheet-rich hetero-aggregates. The formation of Aβ-medin hetero-aggregates did not hinder Aβ and medin from recruiting additional Aβ and medin peptides to grow into larger β-sheet-rich aggregates. The β-barrel oligomer intermediates observed in the self-aggregations of Aβ and medin were also present during their co-aggregation. In cross-seeding simulations, preformed Aβ fibrils could recruit isolated medin monomers to form elongated β-sheets. Overall, our comprehensive simulations suggested that the cross-interaction between Aβ and medin may contribute to their pathological aggregation, given the inherent amyloidogenic tendencies of both medin and Aβ. Targeting medin, therefore, could offer a novel therapeutic approach to preserving brain function during aging and AD by improving vascular health.

Keywords:  amyloid aggregation; amyloid-β; co-aggregation; cross-seeding; discrete molecular dynamics; medin

DOI:  https://doi.org/10.1093/bib/bbad526
bioRxiv. 2024 Jan 01. pii: 2023.12.30.573738. [Epub ahead of print]

Constitutive Endolysosomal Perforation in Neurons allows Induction of α-Synuclein Aggregation by Internalized Pre-Formed Fibrils.

Anwesha Sanyal, Gustavo Scanavachi, Elliott Somerville, Anand Saminathan, Athul Nair, Athanasios Oikonomou, Nikos S Hatzakis, Tom Kirchhausen.

The endocytic pathway is both an essential route of molecular uptake in cells and a potential entry point for pathology-inducing cargo. The cell-to-cell spread of cytotoxic aggregates, such as those of α-synuclein (α-syn) in Parkinson's Disease (PD), exemplifies this duality. Here we used a human iPSC-derived induced neuronal model (iNs) prone to death mediated by aggregation in late endosomes and lysosomes of endogenous α-syn, seeded by internalized pre-formed fibrils of α-syn (PFFs). This PFF-mediated death was not observed with parental iPSCs or other non-neuronal cells. Using live-cell optical microscopy to visualize the read out of biosensors reporting endo-lysosome wounding, we discovered that up to about 10% of late endosomes and lysosomes in iNs exhibited spontaneous constitutive perforations, regardless of the presence of internalized PFFs. This wounding, absent in parental iPSCs and non-neuronal cells, corresponded to partial damage by nanopores in the limiting membranes of a subset of endolysosomes directly observed by volumetric focused ion beam scanning electron microscopy (FIB-SEM) in iNs and in CA1 pyramidal neurons from mouse brain, and not found in iPSCs or in other non-neuronal cells in culture or in mouse liver and skin. We suggest that the compromised limiting membranes in iNs and neurons in general are the primary conduit for cytosolic α-syn to access PFFs entrapped within endo-lysosomal lumens, initiating PFF-mediated α-syn aggregation. Significantly, eradicating the intrinsic endolysosomal perforations in iNs by inhibiting the endosomal Phosphatidylinositol-3-Phosphate/Phosphatidylinositol 5-Kinase (PIKfyve kinase) using Apilimod or Vacuolin-1 markedly reduced PFF-induced α-syn aggregation, despite PFFs continuing to enter the endolysosomal compartment. Crucially, this intervention also diminished iN death associated with PFF incubation. Our results reveal the surprising presence of intrinsically perforated endo-lysosomes in neurons, underscoring their crucial early involvement in the genesis of toxic α-syn aggregates induced by internalized PFFs. This discovery offers a basis for employing PIKfyve kinase inhibition as a potential therapeutic strategy to counteract synucleinopathies.

DOI: https://doi.org/10.1101/2023.12.30.573738
J Chem Inf Model. 2024 Jan 23.

Using Generative Modeling to Endow with Potency Initially Inert Compounds with Good Bioavailability and Low Toxicity.

Robert I Horne, Jared Wilson-Godber, Alicia González Díaz, Z Faidon Brotzakis, Srijit Seal, Rebecca C Gregory, Andrea Possenti, Sean Chia, Michele Vendruscolo.

In the early stages of drug development, large chemical libraries are typically screened to identify compounds of promising potency against the chosen targets. Often, however, the resulting hit compounds tend to have poor drug metabolism and pharmacokinetics (DMPK), with negative developability features that may be difficult to eliminate. Therefore, starting the drug discovery process with a "null library", compounds that have highly desirable DMPK properties but no potency against the chosen targets, could be advantageous. Here, we explore the opportunities offered by machine learning to realize this strategy in the case of the inhibition of α-synuclein aggregation, a process associated with Parkinson's disease. We apply MolDQN, a generative machine learning method, to build an inhibitory activity against α-synuclein aggregation into an initial inactive compound with good DMPK properties. Our results illustrate how generative modeling can be used to endow initially inert compounds with desirable developability properties.

DOI: https://doi.org/10.1021/acs.jcim.3c01777
Cells. 2024 Jan 18. pii: 188. [Epub ahead of print]13(2):

The Multifaceted Role of Cofilin in Neurodegeneration and Stroke: Insights into Pathogenesis and Targeting as a Therapy.

Faheem Shehjar, Daniyah A Almarghalani, Reetika Mahajan, Syed A-M Hasan, Zahoor A Shah.

  This comprehensive review explores the complex role of cofilin, an actin-binding protein, across various neurodegenerative diseases (Alzheimer's, Parkinson's, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's) and stroke. Cofilin is an essential protein in cytoskeletal dynamics, and any dysregulation could lead to potentially serious complications. Cofilin's involvement is underscored by its impact on pathological hallmarks like Aβ plaques and α-synuclein aggregates, triggering synaptic dysfunction, dendritic spine loss, and impaired neuronal plasticity, leading to cognitive decline. In Parkinson's disease, cofilin collaborates with α-synuclein, exacerbating neurotoxicity and impairing mitochondrial and axonal function. ALS and frontotemporal dementia showcase cofilin's association with genetic factors like C9ORF72, affecting actin dynamics and contributing to neurotoxicity. Huntington's disease brings cofilin into focus by impairing microglial migration and influencing synaptic plasticity through AMPA receptor regulation. Alzheimer's, Parkinson's, and schizophrenia exhibit 14-3-3 proteins in cofilin dysregulation as a shared pathological mechanism. In the case of stroke, cofilin takes center stage, mediating neurotoxicity and neuronal cell death. Notably, there is a potential overlap in the pathologies and involvement of cofilin in various diseases. In this context, referencing cofilin dysfunction could provide valuable insights into the common pathologies associated with the aforementioned conditions. Moreover, this review explores promising therapeutic interventions, including cofilin inhibitors and gene therapy, demonstrating efficacy in preclinical models. Challenges in inhibitor development, brain delivery, tissue/cell specificity, and long-term safety are acknowledged, emphasizing the need for precision drug therapy. The call to action involves collaborative research, biomarker identification, and advancing translational efforts. Cofilin emerges as a pivotal player, offering potential as a therapeutic target. However, unraveling its complexities requires concerted multidisciplinary efforts for nuanced and effective interventions across the intricate landscape of neurodegenerative diseases and stroke, presenting a hopeful avenue for improved patient care.

Keywords:  cofilin; cofilin inhibition; cofilin signaling; neurodegenerative diseases; neuroinflammation

DOI:  https://doi.org/10.3390/cells13020188
Biomolecules. 2024 Jan 16. pii: 118. [Epub ahead of print]14(1):

Current Technologies Unraveling the Significance of Post-Translational Modifications (PTMs) as Crucial Players in Neurodegeneration.

Saima Zafar, Shehzadi Irum Fatima, Matthias Schmitz, Inga Zerr.

  Neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, and Huntington's disease, are identified and characterized by the progressive loss of neurons and neuronal dysfunction, resulting in cognitive and motor impairment. Recent research has shown the importance of PTMs, such as phosphorylation, acetylation, methylation, ubiquitination, sumoylation, nitration, truncation, O-GlcNAcylation, and hydroxylation, in the progression of neurodegenerative disorders. PTMs can alter protein structure and function, affecting protein stability, localization, interactions, and enzymatic activity. Aberrant PTMs can lead to protein misfolding and aggregation, impaired degradation, and clearance, and ultimately, to neuronal dysfunction and death. The main objective of this review is to provide an overview of the PTMs involved in neurodegeneration, their underlying mechanisms, methods to isolate PTMs, and the potential therapeutic targets for these disorders. The PTMs discussed in this article include tau phosphorylation, α-synuclein and Huntingtin ubiquitination, histone acetylation and methylation, and RNA modifications. Understanding the role of PTMs in neurodegenerative diseases may provide new therapeutic strategies for these devastating disorders.

Keywords:  Alzheimer’s disease; PTM; Parkinson’s disease; neuronal dysfunction; proteomics; synuclein; tau phosphorylation

DOI:  https://doi.org/10.3390/biom14010118
Int J Mol Sci. 2024 Jan 17. pii: 1135. [Epub ahead of print]25(2):

The 75-99 C-Terminal Peptide of URG7 Protein Promotes α-Synuclein Disaggregation.

Jany Dandurand, Magnus Monné, Valérie Samouillan, Martina Rosa, Alessandro Laurita, Alessandro Pistone, Donatella Bisaccia, Ilenia Matera, Faustino Bisaccia, Angela Ostuni.

  Up Regulation Gene seven (URG7) is the pseudogene 2 of the transporter ABCC6. The translated URG7 protein is localized with its single transmembrane α-helix in the endoplasmic reticulum (ER) membrane, orienting the N- and C-terminal regions in the lumen and cytoplasm, respectively, and it plays a crucial role in the folding of ER proteins. Previously, the C-terminal region of URG7 (PU, residues 75-99) has been shown to modify the aggregation state of α-synuclein in the lysate of HepG2 cells. PU analogs were synthesized, and their anti-aggregation potential was tested in vitro on α-synuclein obtained using recombinant DNA technology. Circular dichroism (CD), differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy, and microscopic techniques were used to assess the sample's behavior. The results show that the peptides studied by themselves are prone to clathrate-like structure formation of variable stability. Aggregation of α-synuclein is accompanied by desolvation of its peptide chain and an increase in intermolecular β-sheets. The PU analogs all interact with α-synuclein aggregates and those possessing the most stable clathrate-like structures have the highest disaggregating effect. These findings suggest that the C-terminal region of URG7 may have a role in interacting and modulating α-synuclein structures and could be used to generate interesting therapeutic candidates as disaggregators of α-synuclein.

Keywords:  URG7; bioinformatics; clathrate-like structures; intermolecular β-sheets; peptides; α-synuclein

DOI:  https://doi.org/10.3390/ijms25021135
Cell Mol Life Sci. 2024 Jan 27. 81(1): 61

α-Synuclein reduces acetylserotonin O-methyltransferase mediated melatonin biosynthesis by microtubule-associated protein 1 light chain 3 beta-related degradation pathway.

Congcong Jia, Lulu Tian, Cheng Cheng, Jun Zhang, Murad Al-Nusaif, Tianbai Li, Huijia Yang, Yushan Lin, Song Li, Weidong Le.

  Previous studies have demonstrated that α-synuclein (α-SYN) is closely associated with rapid eye movement sleep behavior disorder (RBD) related to several neurodegenerative disorders. However, the exact molecular mechanisms are still rarely investigated. In the present study, we found that in the α-SYNA53T induced RBD-like behavior mouse model, the melatonin level in the plasma and pineal gland were significantly decreased. To elucidate the underlying mechanism of α-SYN-induced melatonin reduction, we investigated the effect of α-SYN in melatonin biosynthesis. Our findings showed that α-SYN reduced the level and activity of melatonin synthesis enzyme acetylserotonin O-methyltransferase (ASMT) in the pineal gland and in the cell cultures. In addition, we found that microtubule-associated protein 1 light chain 3 beta (LC3B) as an important autophagy adapter is involved in the degradation of ASMT. Immunoprecipitation assays revealed that α-SYN increases the binding between LC3B and ASMT, leading to ASMT degradation and a consequent reduction in melatonin biosynthesis. Collectively, our results demonstrate the molecular mechanisms of α-SYN in melatonin biosynthesis, indicating that melatonin is an important molecule involved in the α-SYN-associated RBD-like behaviors, which may provide a potential therapeutic target for RBD of Parkinson's disease.

Keywords:  ASMT; LC3B; Melatonin; Parkinson’s disease; α-Synuclein

DOI:  https://doi.org/10.1007/s00018-023-05053-7
Mol Neurodegener. 2024 Jan 25. 19(1): 12

Mitochondrial CISD1/Cisd accumulation blocks mitophagy and genetic or pharmacological inhibition rescues neurodegenerative phenotypes in Pink1/parkin models.

Aitor Martinez, Alvaro Sanchez-Martinez, Jake T Pickering, Madeleine J Twyning, Ana Terriente-Felix, Po-Lin Chen, Chun-Hong Chen, Alexander J Whitworth.

   BACKGROUND: Mitochondrial dysfunction and toxic protein aggregates have been shown to be key features in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease (PD). Functional analysis of genes linked to PD have revealed that the E3 ligase Parkin and the mitochondrial kinase PINK1 are important factors for mitochondrial quality control. PINK1 phosphorylates and activates Parkin, which in turn ubiquitinates mitochondrial proteins priming them and the mitochondrion itself for degradation. However, it is unclear whether dysregulated mitochondrial degradation or the toxic build-up of certain Parkin ubiquitin substrates is the driving pathophysiological mechanism leading to PD. The iron-sulphur cluster containing proteins CISD1 and CISD2 have been identified as major targets of Parkin in various proteomic studies.
METHODS: We employed in vivo Drosophila and human cell culture models to study the role of CISD proteins in cell and tissue viability as well as aged-related neurodegeneration, specifically analysing aspects of mitophagy and autophagy using orthogonal assays.
RESULTS: We show that the Drosophila homolog Cisd accumulates in Pink1 and parkin mutant flies, as well as during ageing. We observed that build-up of Cisd is particularly toxic in neurons, resulting in mitochondrial defects and Ser65-phospho-Ubiquitin accumulation. Age-related increase of Cisd blocks mitophagy and impairs autophagy flux. Importantly, reduction of Cisd levels upregulates mitophagy in vitro and in vivo, and ameliorates pathological phenotypes in locomotion, lifespan and neurodegeneration in Pink1/parkin mutant flies. In addition, we show that pharmacological inhibition of CISD1/2 by rosiglitazone and NL-1 induces mitophagy in human cells and ameliorates the defective phenotypes of Pink1/parkin mutants.
CONCLUSION: Altogether, our studies indicate that Cisd accumulation during ageing and in Pink1/parkin mutants is a key driver of pathology by blocking mitophagy, and genetically and pharmacologically inhibiting CISD proteins may offer a potential target for therapeutic intervention.

Keywords:  Ageing; Autophagy; CISD1; CISD2; Cisd; Mitochondria; Mitophagy; Neurodegeneration; PINK1; Parkin; Parkinson’s disease

DOI:  https://doi.org/10.1186/s13024-024-00701-3
Behav Brain Res. 2024 Jan 22. pii: S0166-4328(24)00027-5. [Epub ahead of print] 114871

Acupuncture Activates IRE1/XBP1 Endoplasmic Reticulum Stress Pathway in Parkinson's Disease Model Rats.

Zhifang Wang, Menglin Kou, Qiyue Deng, Haotian Yu, Jilin Mei, Jing Gao, Wen Fu, Baile Ning.

  Acupuncture has demonstrated its efficacy as a treatment for Parkinson's disease (PD). Thus, the objective of this study was to investigate the potential mechanisms underlying acupuncture's effects on PD treatment. Our approach involved several steps. Firstly, we assessed the behavioral changes in PD rats, the modulation of dopamine (DA) and 5-hydroxytryptamine (5-HT) levels in the striatum, as well as the alteration in α-synuclein (α-syn) levels in the midbrain, aiming to evaluate the efficacy of acupuncture in PD treatment. Secondly, we selected endoplasmic reticulum (ER) stress inhibitors and activators to assess the impact of ER stress on PD rats. Lastly, we utilized an IRE1 inhibitor to observe the influence of acupuncture on the IRE1/XBP1 pathway in PD rats. The findings of this study revealed that acupuncture improved the autonomous motor function, balance ability, coordination, and sensory motor integration function in the PD model rats. Additionally, it increased the levels of DA and 5-HT in the striatum while decreasing the levels of α-syn in the midbrain. Acupuncture also activated the expression of ER stress in the midbrain and upregulated the expression of IRE1/XBP1 in the striatum of PD model rats. Based on these results, we concluded that acupuncture may enhance the behavior of PD rats by activating the IRE1/XBP1 ER stress pathway, associated with the reduction of midbrain α-syn expression and the increase in striatal DA and 5-HT levels in unilateral 6-OHDA lesioned rats.

Keywords:  IRE1/XBP1 pathway; Parkinson's disease; acupuncture; endoplasmic reticulum stress; α-synuclein

DOI:  https://doi.org/10.1016/j.bbr.2024.114871
Nanoscale. 2024 Jan 23.

Cooperative dissolution of peptidomimetic vesicles and amyloid β fibrils.

Soumik Dinda, Debasis Ghosh, Thimmaiah Govindaraju.

The aggregation of amyloid proteins in the brain is a significant neurotoxic event that contributes to neurodegenerative disorders. The aggregation of amyloid beta (Aβ), particularly Aβ42 monomers, into various forms such as oligomers, protofibrils, fibrils, and amyloid plaques is a key pathological feature in Alzheimer's disease. As a result, Aβ42 is a primary target and the development of molecular strategies for the dissolution of Aβ42 aggregates is considered a promising approach to mitigating Alzheimer's disease pathology. A set of pyrene-conjugated peptidomimetics derived from Aβ14-23 (AkdcPy, AkdmPy, and AkdnPy) by incorporating an unnatural amino acid [kd: cyclo(Lys-Asp)] were studied for their ability to modulate Aβ42 aggregation. AkdcPy and AkdmPy formed vesicular structures in aqueous media. The vesicles of AkdmPy loaded with the neuroprotective compound berberine (Ber), dissipated mutually in the presence of preformed Aβ42 fibrils. During this process, the active drug Ber was released. This work is expected to inspire the development of drug-loaded peptidomimetic-based therapeutic formulations to modulate disorders associated with amyloid toxicity.

DOI: https://doi.org/10.1039/d3nr04847k
Neurobiol Dis. 2024 Jan 21. pii: S0969-9961(24)00013-5. [Epub ahead of print]192 106414

PAD2 dysregulation and aberrant protein citrullination feature prominently in reactive astrogliosis and myelin protein aggregation in sporadic ALS.

Issa O Yusuf, Sepideh Parsi, Lyle W Ostrow, Robert H Brown, Paul R Thompson, Zuoshang Xu.

  Alteration in protein citrullination (PC), a common posttranslational modification (PTM), contributes to pathogenesis in various inflammatory disorders. We previously reported that PC and protein arginine deiminase 2 (PAD2), the predominant enzyme isoform that catalyzes this PTM in the central nervous system (CNS), are altered in mouse models of amyotrophic lateral sclerosis (ALS). We now demonstrate that PAD2 expression and PC are altered in human postmortem ALS spinal cord and motor cortex compared to controls, increasing in astrocytes while trending lower in neurons. Furthermore, PC is enriched in protein aggregates that contain the myelin proteins PLP and MBP in ALS. These results confirm our findings in ALS mouse models and suggest that altered PAD2 and PC contribute to neurodegeneration in ALS.

Keywords:  Deimination; Myelin degeneration; Neurodegeneration; Neurodegenerative disease; Neuroinflammation; Protein aggregation

DOI:  https://doi.org/10.1016/j.nbd.2024.106414
JACS Au. 2024 Jan 22. 4(1): 92-100

Mutations in Tau Protein Promote Aggregation by Favoring Extended Conformations.

Kevin Pounot, Clara Piersson, Andrew K Goring, Frédéric Rosu, Valérie Gabelica, Martin Weik, Songi Han, Yann Fichou.

Amyloid aggregation of the intrinsically disordered protein (IDP) tau is involved in several diseases, called tauopathies. Some tauopathies can be inherited due to mutations in the gene encoding tau, which might favor the formation of tau amyloid fibrils. This work aims at deciphering the mechanisms through which the disease-associated single-point mutations promote amyloid formation. We combined biochemical and biophysical characterization, notably, small-angle X-ray scattering (SAXS), to study six different FTDP-17 derived mutations. We found that the mutations promote aggregation to different degrees and can modulate tau conformational ensembles, intermolecular interactions, and liquid-liquid phase separation propensity. In particular, we found a good correlation between the aggregation lag time of the mutants and their radii of gyration. We show that mutations disfavor intramolecular protein interactions, which in turn favor extended conformations and promote amyloid aggregation. This work proposes a new connection between the structural features of tau monomers and their propensity to aggregate, providing a novel assay to evaluate the aggregation propensity of IDPs.

DOI: https://doi.org/10.1021/jacsau.3c00550
Int J Mol Sci. 2024 Jan 21. pii: 1299. [Epub ahead of print]25(2):

Network Analysis Performed on Transcriptomes of Parkinson's Disease Patients Reveals Dysfunction in Protein Translation.

Simone D'Angiolini, Maria Lui, Emanuela Mazzon, Marco Calabrò.

  Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra region of the brain. The hallmark pathological feature of PD is the accumulation of misfolded proteins, leading to the formation of intracellular aggregates known as Lewy bodies. Recent data evidenced how disruptions in protein synthesis, folding, and degradation are events commonly observed in PD and may provide information on the molecular background behind its etiopathogenesis. In the present study, we used a publicly available transcriptomic microarray dataset of peripheral blood of PD patients and healthy controls (GSE6613) to investigate the potential dysregulation of elements involved in proteostasis-related processes at the transcriptomic level. Our bioinformatics analysis revealed 375 differentially expressed genes (DEGs), of which 281 were down-regulated and 94 were up-regulated. Network analysis performed on the observed DEGs highlighted a cluster of 36 elements mainly involved in the protein synthesis processes. Different enriched ontologies were related to translation initiation and regulation, ribosome structure, and ribosome components nuclear export. Overall, this data consistently points to a generalized impairment of the translational machinery and proteostasis. Dysregulation of these mechanics has been associated with PD pathogenesis. Understanding the precise regulation of such processes may shed light on the molecular mechanisms of PD and provide potential data for early diagnosis.

Keywords:  Parkinson’s disease; network analysis; peripheral blood; protein synthesis; transcriptomic data

DOI:  https://doi.org/10.3390/ijms25021299
Biol Pharm Bull. 2024 ;47(1): 253-258

Wild-Type DCTN1 Suppresses the Aggregation of DCTN1 Mutants Associated with Perry Disease.

Yuto Fukui, Hisashi Shirakawa, Shuji Kaneko, Kazuki Nagayasu.

  Perry disease, a rare autosomal dominant neurodegenerative disorder, is characterized by parkinsonism, depression or apathy, unexpected weight loss, and central hypoventilation. Genetic analyses have revealed a strong association between point mutations in the dynactin I gene (DCTN1) coding p150glued and Perry disease. Although previous reports have suggested a critical role of p150glued aggregation in Perry disease pathology, whether and how p150glued mutations affect protein aggregation is not fully understood. In this study, we comprehensively investigated the intracellular distribution of the p150glued mutants in HEK293T cells. We further assessed the effect of co-overexpression of the wild-type p150glued protein with mutants on the formation of mutant aggregates. Notably, overexpression of p150glued mutants identified in healthy controls, which is also associated with amyotrophic lateral sclerosis, showed a thread-like cytoplasmic distribution, similar to the wild-type p150glued. In contrast, p150glued mutants in Perry disease and motor neuron disease caused aggregation. In addition, the co-overexpression of the wild-type protein with p150glued mutants in Perry disease suppressed aggregate formation. In contrast, the p150glued aggregation of motor neuron disease mutants was less affected by the wild-type p150glued. Further investigation of the mechanism of aggregate formation, contents of the aggregates, and biological mechanisms of Perry disease could help develop novel therapeutics.

Keywords:  Perry disease; aggregates; amyotrophic lateral sclerosis; dynactin I gene (DCTN1); p150

DOI:  https://doi.org/10.1248/bpb.b23-00828