bims-proned 2024-07-07 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024‒07‒07
fifteen papers selected by
Verena Kohler, Umeå University

Mechanistic Insight into Intestinal α-Synuclein Aggregation in Parkinson's Disease Using a Laser-Printed Electrochemical Sensor.
Lysophosphatidylcholine binds α-synuclein and prevents its pathological aggregation.
Exploring α-synuclein stability under the external electrostatic fields: Effect of repeat unit.
Cannabidiol and Neurodegeneration: From Molecular Mechanisms to Clinical Benefits.
Presenilin deficiency enhances tau phosphorylation and its secretion.
VAMP2 chaperones α-synuclein in synaptic vesicle co-condensates.
Solid-state NMR assignment of α-synuclein polymorph prepared from helical intermediate.
Synthesis and bio-activities of bifunctional tetrahydrosalen Cu (II) chelators with potential efficacy in Alzheimer's disease therapy.
Solid-state NMR backbone chemical shift assignments of α-synuclein amyloid fibrils at fast MAS regime.
Molecular Insight into the Effect of HIV-TAT Protein on Amyloid-β Peptides.
BACE1 inhibitor drugs for the treatment of Alzheimer's disease: Lessons learned, challenges to overcome, and future prospects†.
Epitope-specific antibody fragments block aggregation of AGelD187N, an aberrant peptide in gelsolin amyloidosis.
Therapeutic Implications and Regulations of Protein Post-translational Modifications in Parkinsons Disease.
TDP-43 in nuclear condensates: where, how, and why.
Neurodegenerative diseases associated with the disruption of proteostasis and their therapeutic strategies using chemical chaperones.

ACS Chem Neurosci. 2024 Jul 03.

Mechanistic Insight into Intestinal α-Synuclein Aggregation in Parkinson's Disease Using a Laser-Printed Electrochemical Sensor.

Julia M Balsamo, Keren Zhou, Vinay Kammarchedu, Aida Ebrahimi, Elizabeth N Bess.

  Aggregated deposits of the protein α-synuclein and depleting levels of dopamine in the brain correlate with Parkinson's disease development. Treatments often focus on replenishing dopamine in the brain; however, the brain might not be the only site requiring attention. Aggregates of α-synuclein appear to accumulate in the gut years prior to the onset of any motor symptoms. Enteroendocrine cells (specialized gut epithelial cells) may be the source of intestinal α-synuclein, as they natively express this protein. Enteroendocrine cells are constantly exposed to gut bacteria and their metabolites because they border the gut lumen. These cells also express the dopamine metabolic pathway and form synapses with vagal neurons, which innervate the gut and brain. Through this connection, Parkinson's disease pathology may originate in the gut and spread to the brain over time. Effective therapeutics to prevent this disease progression are lacking due to a limited understanding of the mechanisms by which α-synuclein aggregation occurs in the gut. We previously proposed a gut bacterial metabolic pathway responsible for the initiation of α-synuclein aggregation that is dependent on the oxidation of dopamine. Here, we develop a new tool, a laser-induced graphene-based electrochemical sensor chip, to track α-synuclein aggregation and dopamine level over time. Using these sensor chips, we evaluated diet-derived catechols dihydrocaffeic acid and caffeic acid as potential inhibitors of α-synuclein aggregation. Our results suggest that these molecules inhibit dopamine oxidation. We also found that these dietary catechols inhibit α-synuclein aggregation in STC-1 enteroendocrine cells. These findings are critical next steps to reveal new avenues for targeted therapeutics to treat Parkinson's disease, specifically in the context of functional foods that may be used to reshape the gut environment.

Keywords:  LIG sensor; Parkinson’s disease; dopamine; iron; polyphenols; α-synuclein

DOI:  https://doi.org/10.1021/acschemneuro.4c00106
Natl Sci Rev. 2024 Jun;11(6): nwae182

Lysophosphatidylcholine binds α-synuclein and prevents its pathological aggregation.

Chunyu Zhao, Jia Tu, Chuchu Wang, Wenbin Liu, Jinge Gu, Yandong Yin, Shengnan Zhang, Dan Li, Jiajie Diao, Zheng-Jiang Zhu, Cong Liu.

  Accumulation of aggregated α-synuclein (α-syn) in Lewy bodies is the pathological hallmark of Parkinson's disease (PD). Genetic mutations in lipid metabolism are causative for a subset of patients with Parkinsonism. The role of α-syn's lipid interactions in its function and aggregation is recognized, yet the specific lipids involved and how lipid metabolism issues trigger α-syn aggregation and neurodegeneration remain unclear. Here, we found that α-syn shows a preference for binding to lysophospholipids (LPLs), particularly targeting lysophosphatidylcholine (LPC) without relying on electrostatic interactions. LPC is capable of maintaining α-syn in a compact conformation, significantly reducing its propensity to aggregate both in vitro and within cellular environments. Conversely, a reduction in the production of cellular LPLs is associated with an increase in α-syn accumulation. Our work underscores the critical role of LPLs in preserving the natural conformation of α-syn to inhibit improper aggregation, and establishes a potential connection between lipid metabolic dysfunction and α-syn aggregation in PD.

Keywords:  Parkinson's disease; lysophosphatidylcholine, aggregation; α-synuclein

DOI:  https://doi.org/10.1093/nsr/nwae182
J Struct Biol. 2024 Jul 02. pii: S1047-8477(24)00049-2. [Epub ahead of print] 108109

Exploring α-synuclein stability under the external electrostatic fields: Effect of repeat unit.

Javokhir Khursandov, Rasulbek Mashalov, Mukhriddin Makhkamov, Farkhad Turgunboev, Avez Sharipov, Jamoliddin Razzokov.

  Parkinson's disease (PD) is a category of neurodegenerative disorders (ND) that currently lack comprehensive and definitive treatment strategies. The etiology of PD can be attributed to the presence and aggregation of a protein known as α-synuclein. Researchers have observed that the application of an external electrostatic field holds the potential to induce the separation of the fibrous structures into peptides. To comprehend this phenomenon, our investigation involved simulations conducted on the α-synuclein peptides through the application of Molecular Dynamics (MD) simulation techniques under the influence of a 0.1 V/nm electric field. The results obtained from the MD simulations revealed that in the presence of external electric field, the monomer and oligomeric forms of α-synuclein are experienced significant conformational changes which could prevent them from further aggregation. However, as the number of peptide units in the model system increases, forming trimers and tetramers, the stability against the electric field also increases. This enhanced stability in larger aggregates indicates a critical threshold in α-synuclein assembly where the electric field's effectiveness in disrupting the aggregation diminishes. Therefore, our findings suggest that early diagnosis and intervention could be crucial in preventing PD progression. When α-synuclein predominantly exists in its monomeric or dimeric form, applying even a lower electric field could effectively disrupt the initial aggregation process. Inhibition of α-synuclein fibril formation at early stages might serve as a viable solution to combat PD by halting the formation of more stable and pathogenic α-synuclein fibrils.

Keywords:  Electric field; Molecular dynamics; Parkinson’s disease; α-synuclein fibril

DOI:  https://doi.org/10.1016/j.jsb.2024.108109
Ageing Res Rev. 2024 Jul 03. pii: S1568-1637(24)00204-6. [Epub ahead of print] 102386

Cannabidiol and Neurodegeneration: From Molecular Mechanisms to Clinical Benefits.

Saurabh Kumar Jha, Vinod Kumar Nelson, Punna Rao Suryadevara, Siva Prasad Panda, Chitikela P Pullaiah, Mohana Vamsi Nuli, Mehnaz Kamal, Mohd Imran, Saijyothi Ausali, Mosleh Mohammad Abomughaid, Rashi Srivastava, Rahul Deka, Pingal Pritam, Neha Gupta, Harishankar Shyam, Indrakant K Singh, Bindhy Wasini Pandey, Saikat Dewanjee, Niraj Kumar Jha, Seid Mahdi Jafari.

  Neurodegenerative disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis are severe and life-threatening conditions in which significant damage of functional neurons occurs to produce malfunction of psycho-motor functions. NDs are an important cause of death in the elderly population worldwide. These disorders are commonly associated with the progression of age, oxidative stress, and environmental pollutants, which are the major etiological factors. Abnormal aggregation of specific proteins such as α-synuclein, amyloid-β, huntingtin, and tau, and accumulation of its associated oligomers in neurons are the hallmark pathological features of NDs. Existing therapeutic options for NDs are only symptomatic relief and do not address root-causing factors, such as protein aggregation, oxidative stress, and neuroinflammation. Cannabidiol is a non-psychotic natural cannabinoid obtained from Cannabis sativa that possesses multiple pharmacological actions, including antioxidant, anti-inflammatory, and neuroprotective effects in various NDs and other neurological disorders both in vitro and in vivo. Cannabidiol has gained attention as a promising therapeutic drug candidate for the management of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, by inhibiting protein aggregation, free radicals, and neuroinflammation. In parallel, CBD has shown positive results in other neurological disorders, such as epilepsy, depression, schizophrenia, and anxiety, as well as adjuvant treatment with existing standard therapeutic agents. Hence, the present review focuses on exploring the possible molecular mechanisms in controlling various neurological disorders as well as its clinical applications in NDs including epilepsy, depression and anxiety. In this way, the current review will serve as a standalone reference for the researchers working in this area.

Keywords:  Cannabidiol; Protein aggregations; ROS; anti-inflammatory; anti-oxidant; clearance of protein aggregates; inflammation; neurodegenerative disease

DOI:  https://doi.org/10.1016/j.arr.2024.102386
J Neurochem. 2024 Jul 01.

Presenilin deficiency enhances tau phosphorylation and its secretion.

Yang Sun, Sadequl Islam, Yuan Gao, Tomohisa Nakamura, Taisuke Tomita, Makoto Michikawa, Kun Zou.

  Alzheimer's disease (AD) is characterized by the accumulation of abnormally folded amyloid β-protein (Aβ) in the brain parenchyma and phosphorylated tau in neurons. Presenilin (PS, PSEN) 1 and PS2 are essential components of γ-secretase, which is responsible for the cleavage of amyloid precursor protein (APP) to generate Aβ. PSEN mutations are associated with tau aggregation in frontotemporal dementia, regardless of the presence or absence of Aβ pathology. However, the mechanism by which PS regulates tau aggregation is still unknown. Here, we found that tau phosphorylation and secretion were significantly increased in PS double-knock-out (PS1/2-/-) fibroblasts compared with wild-type fibroblasts. Tau-positive vesicles in the cytoplasm were significantly increased in PS1/2-/- fibroblasts. Active GSK-3β was increased in PS1/2-/- fibroblasts, and inhibiting GSK3β activity in PS1/2-/- fibroblasts resulted in decreased tau phosphorylation and secretion. Transfection of WT human PS1 and PS2 reduced the secretion of phosphorylated tau and active GSK-3β in PS1/2-/- fibroblasts. However, PS1D257A without γ-secretase activity did not decrease the secretion of phosphorylated tau. Furthermore, nicastrin deficiency also increased tau phosphorylation and secretion. These results suggest that deficient PS complex maturation may increase tau phosphorylation and secretion. Thus, our studies discover a new pathway by which PS regulates tau phosphorylation/secretion and pathology independent of Aβ and suggest that PS serves as a potential therapeutic target for treating neurodegenerative diseases involving tau aggregation.

Keywords:  Alzheimer's disease; GSK‐3β; phosphorylation; presenilin; secretion; tau

DOI:  https://doi.org/10.1111/jnc.16155
Nat Cell Biol. 2024 Jul 01.

VAMP2 chaperones α-synuclein in synaptic vesicle co-condensates.

Chuchu Wang, Kai Zhang, Bin Cai, Jillian E Haller, Kathryn E Carnazza, Jiaojiao Hu, Chunyu Zhao, Zhiqi Tian, Xiao Hu, Daniel Hall, Jiali Qiang, Shouqiao Hou, Zhenying Liu, Jinge Gu, Yaoyang Zhang, Kim B Seroogy, Jacqueline Burré, Yanshan Fang, Cong Liu, Axel T Brunger, Dan Li, Jiajie Diao.

α-Synuclein (α-Syn) aggregation is closely associated with Parkinson's disease neuropathology. Physiologically, α-Syn promotes synaptic vesicle (SV) clustering and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly. However, the underlying structural and molecular mechanisms are uncertain and it is not known whether this function affects the pathological aggregation of α-Syn. Here we show that the juxtamembrane region of vesicle-associated membrane protein 2 (VAMP2)-a component of the SNARE complex that resides on SVs-directly interacts with the carboxy-terminal region of α-Syn through charged residues to regulate α-Syn's function in clustering SVs and promoting SNARE complex assembly by inducing a multi-component condensed phase of SVs, α-Syn and other components. Moreover, VAMP2 binding protects α-Syn against forming aggregation-prone oligomers and fibrils in these condensates. Our results suggest a molecular mechanism that maintains α-Syn's function and prevents its pathological amyloid aggregation, the failure of which may lead to Parkinson's disease.

DOI: https://doi.org/10.1038/s41556-024-01456-1
Biomol NMR Assign. 2024 Jul 04.

Solid-state NMR assignment of α-synuclein polymorph prepared from helical intermediate.

Sahil Ahlawat, Surabhi Mehra, Chandrakala M Gowda, Samir K Maji, Vipin Agarwal.

  Synucleinopathies are neurodegenerative diseases characterized by the accumulation of α-synuclein protein aggregates in the neurons and glial cells. Both ex vivo and in vitro α-synuclein fibrils tend to show polymorphism. Polymorphism results in structure variations among fibrils originating from a single polypeptide/protein. The polymorphs usually have different biophysical, biochemical and pathogenic properties. The various pathologies of a single disease might be associated with distinct polymorphs. Similarly, in the case of different synucleinopathies, each condition might be associated with a different polymorph. Fibril formation is a nucleation-dependent process involving the formation of transient and heterogeneous intermediates from monomers. Polymorphs are believed to arise from heterogeneous oligomer populations because of distinct selection mechanisms in different conditions. To test this hypothesis, we isolated and incubated different intermediates during in vitro fibrillization of α-synuclein to form different polymorphs. Here, we report 13C and 15N chemical shifts and the secondary structure of fibrils prepared from the helical intermediate using solid-state nuclear magnetic spectroscopy.

Keywords:  Assignment; Fibrils; Oligomers; Solid-state NMR; α–Synuclein

DOI:  https://doi.org/10.1007/s12104-024-10188-0
J Inorg Biochem. 2024 Jun 19. pii: S0162-0134(24)00160-0. [Epub ahead of print]259 112636

Synthesis and bio-activities of bifunctional tetrahydrosalen Cu (II) chelators with potential efficacy in Alzheimer's disease therapy.

Bin Sun, Heyan Jiang.

  The dyshomeostasis of metal ions in the brain leads to the accumulation of excess metals in extracellular and inter-neuronal locations and the Amyloid β peptide (Aβ) binds these transition metals, which ultimately cause the Aβ aggregation and severe oxidative stress in the brain. The aggregation of Aβ and oxidative stress are important factors to trigger Alzheimer's disease (AD). Metal chelation therapy is a promising approach to removing metals from Aβ-M species and relieve the oxidative stress. Therefore, 4 tetrahydrosalens containing benzothiazole moiety were designed and synthesized. Their biological activities for Alzheimer's disease therapy in vitro were determined by Turbidity assay, BCA protein assay, MTT assay and fluorescent probe of DCFH-DA. The results were comparing with that of non-specific chelator (cliquinol, CQ) and non-benzothiazole functionalized tetrahydrosalens, the results demonstrated that benzothiazole functionalized chelators had more efficient bio-activities in preventing Cu2+-induced Aβ aggregation, attenuating cytotoxicity mediated by Aβ-Cu2+ species and decrease the level of reactive oxygen species (ROS) in Cu2+-Aβ treated PC12 cells than that of cliquinol and non-benzothiazole functionalized analogues.

Keywords:  Alzheimer's disease; Anti-oxidant; Benzothiazole; Synthesis; Tetrahydrosalen; β-Amyloid

DOI:  https://doi.org/10.1016/j.jinorgbio.2024.112636
Biomol NMR Assign. 2024 Jun 29.

Solid-state NMR backbone chemical shift assignments of α-synuclein amyloid fibrils at fast MAS regime.

Zigmantas Toleikis, Piotr Paluch, Ewelina Kuc, Jana Petkus, Darius Sulskis, Mai-Liis Org-Tago, Ago Samoson, Vytautas Smirnovas, Jan Stanek, Alons Lends.

  The α-synuclein (α-syn) amyloid fibrils are involved in various neurogenerative diseases. Solid-state NMR (ssNMR) has been showed as a powerful tool to study α-syn aggregates. Here, we report the 1H, 13C and 15N back-bone chemical shifts of a new α-syn polymorph obtained using proton-detected ssNMR spectroscopy under fast (95 kHz) magic-angle spinning conditions. The manual chemical shift assignments were cross-validated using FLYA algorithm. The secondary structural elements of α-syn fibrils were calculated using 13C chemical shift differences and TALOS software.

Keywords:   1H-detected solid-state NMR; Amyloid fibrils; Fast magic-angle spinning; α-synuclein

DOI:  https://doi.org/10.1007/s12104-024-10186-2
ACS Omega. 2024 Jun 25. 9(25): 27480-27491

Molecular Insight into the Effect of HIV-TAT Protein on Amyloid-β Peptides.

Asis K Jana, Recep Keskin, Fatih Yaşar.

Increased deposition of amyloid-β (Aβ) plaques in the brain is a frequent pathological feature observed in human immunodeficiency virus (HIV)-positive patients. Emerging evidence indicates that HIV regulatory proteins, particularly the transactivator of transcription (TAT) protein, could interact with Aβ peptide, accelerating the formation of Aβ plaques in the brain and potentially contributing to the onset of Alzheimer's disease in individuals with HIV infection. Nevertheless, the molecular mechanisms underlying these processes remain unclear. In the present study, we have used long all-atom molecular dynamics simulations to probe the direct interactions between the TAT protein and Aβ peptide at the molecular level. Sampling over 28.0 μs, our simulations show that TAT protein induces a shift in the Aβ monomer ensemble toward elongated conformations, exposing aggregation-prone regions on the surface and thereby inducing subsequent aggregation. TAT protein also appears to enhance the stability of preformed Aβ fibrils, while increasing the β-sheet content within these fibrils. Our atomistically detailed simulations qualitatively agree with previous in vitro and in vivo studies. Importantly, our simulations identify key interactions between Aβ and the TAT protein that drive the Aβ aggregation process and stabilize the preformed Aβ aggregates, which are particularly challenging to obtain through current experimental techniques.

DOI: https://doi.org/10.1021/acsomega.4c02643
Glob Health Med. 2024 Jun 30. 6(3): 164-168

BACE1 inhibitor drugs for the treatment of Alzheimer's disease: Lessons learned, challenges to overcome, and future prospects†.

Arun K Ghosh.

  Alzheimer's disease (AD), first diagnosed over a century ago, remains one of the major healthcare crises around the globe. Currently, there is no cure or effective treatment. The majority of drug development efforts to date have targeted reduction of amyloid-β peptide (Aβ). Drug development through inhibition of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), resulted in promising early clinical studies. However, nearly all small molecule BACE1 inhibitor drugs failed to live up to expectations in later phase clinical trials, due to toxicity and efficacy issues. This commentary aims to provide a brief review of over two decades of BACE1 inhibitor drug development challenges and efforts for treatment of AD and prospects of future BACE1-based drugs.

Keywords:  Alzheimer disease; BACE1; amyloid; drug development; inhibitor

DOI:  https://doi.org/10.35772/ghm.2024.01033
J Biol Chem. 2024 Jun 27. pii: S0021-9258(24)02008-8. [Epub ahead of print] 107507

Epitope-specific antibody fragments block aggregation of AGelD187N, an aberrant peptide in gelsolin amyloidosis.

Laura Leimu, Patrik Holm, Anna Gąciarz, Oskar Haavisto, Stuart Prince, Ullamari Pesonen, Tuomas Huovinen, Urpo Lamminmäki.

  Aggregation of aberrant fragment of plasma gelsolin, AGelD187N, is a crucial event underlying the pathophysiology of Finnish gelsolin amyloidosis, an inherited form of systemic amyloidosis. The amyloidogenic gelsolin fragment AGelD187N does not play any physiological role in the body, unlike most aggregating proteins related to other protein misfolding diseases. However, no therapeutic agents that specifically and effectively target and neutralize AGelD187N exist. We employed phage display technology to identify novel single-chain variable fragments (scFvs) that bind to different epitopes in the monomeric AGelD187N that were further maturated by variable domain shuffling and converted to antigen-binding fragment (Fab) antibodies. The generated antibody fragments had nanomolar binding affinity for full-length AGelD187N, as evaluated by biolayer interferometry. Importantly, all four Fabs selected for functional studies efficiently inhibited the amyloid formation of full-length AGelD187N as examined by thioflavin fluorescence assay and transmission electron microscopy. Two Fabs, neither of which bound to the previously proposed fibril-forming region of AGelD187N, completely blocked the amyloid formation of AGelD187N. Moreover, no small soluble aggregates, which are considered pathogenic species in protein misfolding diseases, were formed after successful inhibition of amyloid formation by the most promising aggregation inhibitor, as investigated by size exclusion chromatography combined with multi-angle light scattering. We conclude that all regions of the full-length AGelD187N are important in modulating its assembly into fibrils and that the discovered epitope-specific anti-AGelD187N antibody fragments provide a promising starting point for a disease-modifying therapy for gelsolin amyloidosis, which is currently lacking.

Keywords:  aggregation inhibition; amyloid; antibody; antibody engineering; drug discovery; gelsolin amyloidosis (AGel amyloidosis); phage display; protein misfolding

DOI:  https://doi.org/10.1016/j.jbc.2024.107507
Cell Mol Neurobiol. 2024 Jul 03. 44(1): 53

Therapeutic Implications and Regulations of Protein Post-translational Modifications in Parkinsons Disease.

Twinkle Mishra, Shareen Singh, Thakur Gurjeet Singh.

  Parkinsons disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and alpha-synuclein aggregation. This comprehensive review examines the intricate role of post-translational modifications (PTMs) in PD pathogenesis, focusing on DNA methylation, histone modifications, phosphorylation, SUMOylation, and ubiquitination. Targeted PTM modulation, particularly in key proteins like Parkin, DJ1, and PINK1, emerges as a promising therapeutic strategy for mitigating dopaminergic degeneration in PD. Dysregulated PTMs significantly contribute to the accumulation of toxic protein aggregates and dopaminergic neuronal dysfunction observed in PD. Targeting PTMs, including epigenetic strategies, addressing aberrant phosphorylation events, and modulating SUMOylation processes, provides potential avenues for intervention. The ubiquitin-proteasome system, governed by enzymes like Parkin and Nedd4, offers potential targets for clearing misfolded proteins and developing disease-modifying interventions. Compounds like ginkgolic acid, SUMO E1 enzyme inhibitors, and natural compounds like Indole-3-carbinol illustrate the feasibility of modulating PTMs for therapeutic purposes in PD. This review underscores the therapeutic potential of PTM-targeted interventions in modulating PD-related pathways, emphasizing the need for further research in this promising area of Parkinsons disease therapeutics.

Keywords:  Dopaminergic degeneration; PTM-targeted interventions; Parkinsons disease; Post-translational modifications; Protein aggregates

DOI:  https://doi.org/10.1007/s10571-024-01471-8
Biochem Soc Trans. 2024 Jul 03. pii: BST20231447. [Epub ahead of print]

TDP-43 in nuclear condensates: where, how, and why.

Ruaridh Lang, Rachel E Hodgson, Tatyana A Shelkovnikova.

  TDP-43 is an abundant and ubiquitously expressed nuclear protein that becomes dysfunctional in a spectrum of neurodegenerative diseases. TDP-43's ability to phase separate and form/enter biomolecular condensates of varying size and composition is critical for its functionality. Despite the high density of phase-separated assemblies in the nucleus and the nuclear abundance of TDP-43, our understanding of the condensate-TDP-43 relationship in this cellular compartment is only emerging. Recent studies have also suggested that misregulation of nuclear TDP-43 condensation is an early event in the neurodegenerative disease amyotrophic lateral sclerosis. This review aims to draw attention to the nuclear facet of functional and aberrant TDP-43 condensation. We will summarise the current knowledge on how TDP-43 containing nuclear condensates form and function and how their homeostasis is affected in disease.

Keywords:  ALS; TDP-43; condensate; neurodegeneration; nuclear body; paraspeckle; stress response

DOI:  https://doi.org/10.1042/BST20231447
J Biochem. 2024 Jul 02. pii: mvae048. [Epub ahead of print]

Neurodegenerative diseases associated with the disruption of proteostasis and their therapeutic strategies using chemical chaperones.

Takashi Sugiyama, Hideki Nishitoh.

  Aberrant proteostasis is thought to be involved in the pathogenesis of neurodegenerative diseases. Some proteostasis abnormalities are ameliorated by chaperones. Chaperones are divided into three groups: molecular, pharmacological, and chemical. Chemical chaperones intended to alleviate stress in organelles, such as the endoplasmic reticulum (ER), are now being administered clinically. Of the chemical chaperones, 4-phenylbutyrate (4-PBA) has been used as a research reagent, and its mechanism of action includes chaperone effects and the inhibition of histone deacetylase. Moreover, it also binds to the B-site of SEC24 and regulates COPII-mediated transport from the ER. Although its therapeutic effect may not be strong, elucidating the mechanism of action of 4-PBA may contribute to the identification of novel therapeutic targets for neurodegenerative diseases.

Keywords:  4-PBA; COPII vesicles; Chaperone; Endoplasmic reticulum; Neurodegenerative diseases

DOI:  https://doi.org/10.1093/jb/mvae048