bims-proned 2023-12-31 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2023‒12‒31
seven papers selected by
Verena Kohler, Umeå University

Investigating Lysozyme Amyloid Fibril Formation and Structural Variability Dependence on its Initial Folding State Under Different pH Conditions.
Discovery of Quinolinone Hybrids as Dual Inhibitors of Acetylcholinesterase and Aβ Aggregation for Alzheimer's Disease Therapy.
Fluorescent protein tagging promotes phase separation and alters the aggregation pathway of huntingtin exon-1.
Lysophagy protects against propagation of α-synuclein aggregation through ruptured lysosomal vesicles.
Morin suppresses mTORc1/IRE-1α/JNK and IP3R-VDAC-1 pathways: Crucial mechanisms in apoptosis and mitophagy inhibition in experimental Huntington's disease, supported by in silico molecular docking simulations.
NFE2L1/Nrf1 serves as a potential therapeutical target for neurodegenerative diseases.
Understanding the Therapeutic Approaches for Neuroprotection.

Protein Sci. 2023 Dec 27. e4888

Investigating Lysozyme Amyloid Fibril Formation and Structural Variability Dependence on its Initial Folding State Under Different pH Conditions.

Mantas Ziaunys, Kamile Mikalauskaite, Andrius Sakalauskas, Vytautas Smirnovas.

  Protein fibril formation and accumulation is associated with dozens of amyloidoses, including the widespread and yet incurable Alzheimer's and Parkinson's diseases. Currently, there are still several aspects of amyloid aggregation that are not fully understood, which negatively contributes to the development of disease-altering drugs and treatments. One factor which requires a more in-depth analysis is the effect of the environment on both the initial state of amyloidogenic proteins, as well their aggregation process and resulting fibril characteristics. In this work, we examine how lysozyme's folding state influences its amyloid formation kinetics and resulting aggregate structural characteristics under several different pH conditions, ranging from acidic to neutral. We demonstrate that both the initial state of the protein, as well as the solution's pH value have a significant combined effect on the variability of the resulting aggregate secondary structures, as well as their stabilities, interactions with amyloid-specific dye molecules and self-replication properties. This article is protected by copyright. All rights reserved.

Keywords:  Amyloid aggregation; fibril structure; lysozyme

DOI:  https://doi.org/10.1002/pro.4888
ACS Chem Neurosci. 2023 Dec 27.

Discovery of Quinolinone Hybrids as Dual Inhibitors of Acetylcholinesterase and Aβ Aggregation for Alzheimer's Disease Therapy.

Shoaib Manzoor, Moustafa T Gabr, Mohamed S Nafie, Md Kausar Raza, Ashma Khan, Shahid M Nayeem, Reem K Arafa, Nasimul Hoda.

  The development of multitargeted therapeutics has evolved as a promising strategy to identify efficient therapeutics for neurological disorders. We report herein new quinolinone hybrids as dual inhibitors of acetylcholinesterase (AChE) and Aβ aggregation that function as multitargeted ligands for Alzheimer's disease. The quinoline hybrids (AM1-AM16) were screened for their ability to inhibit AChE, BACE1, amyloid fibrillation, α-syn aggregation, and tau aggregation. Among the tested compounds, AM5 and AM10 inhibited AChE activity by more than 80% at single-dose screening and possessed a remarkable ability to inhibit the fibrillation of Aβ42 oligomers at 10 μM. In addition, dose-dependent screening of AM5 and AM10 was performed, giving half-maximal AChE inhibitory concentration (IC50) values of 1.29 ± 0.13 and 1.72 ± 0.18 μM, respectively. In addition, AM5 and AM10 demonstrated concentration-dependent inhibitory profiles for the aggregation of Aβ42 oligomers with estimated IC50 values of 4.93 ± 0.8 and 1.42 ± 0.3 μM, respectively. Moreover, the neuroprotective properties of the lead compounds AM5 and AM10 were determined in SH-SY5Y cells incubated with Aβ oligomers. This work would enable future research efforts aiming at the structural optimization of AM5 and AM10 to develop potent dual inhibitors of AChE and amyloid aggregation. Furthermore, the in vivo assay confirmed the antioxidant activity of compounds AM5 and AM10 through increasing GSH, CAT, and SOD activities that are responsible for scavenging the ROS and restoring its normal level. Blood investigation illustrated the protective activity of the two compounds against lead-induced neurotoxicity through retaining hematological and liver enzymes near normal levels. Finally, immunohistochemistry investigation revealed the inhibitory activity of β-amyloid (Aβ) aggregation.

Keywords:  Alzheimer’s disease; acetylcholinesterase; amyloid-beta; quinolinone hybrids

DOI:  https://doi.org/10.1021/acschemneuro.3c00588
J Biol Chem. 2023 Dec 21. pii: S0021-9258(23)02613-3. [Epub ahead of print] 105585

Fluorescent protein tagging promotes phase separation and alters the aggregation pathway of huntingtin exon-1.

Nitin K Pandey, Jobin Varkey, Anakha Ajayan, Gincy George, Jeannie Chen, Ralf Langen.

  Fluorescent protein tags are convenient tools for tracking the aggregation states of amyloidogenic or phase separating proteins, but the effect of the tags is often not well understood. Here, we investigated the impact of a C-terminal red fluorescent protein (RFP) tag on the phase separation of huntingtin exon-1 (Httex1), an N-terminal portion of the huntingtin protein that aggregates in Huntington's disease. We found that the RFP-tagged Httex1 rapidly formed micron-sized, phase separated states in the presence of a crowding agent. The formed structures had a rounded appearance and were highly dynamic according to electron paramagnetic resonance (EPR) and fluorescence recovery after photobleaching, suggesting that the phase separated state was largely liquid in nature. Remarkably, the untagged protein did not undergo any detectable liquid condensate formation under the same conditions. In addition to strongly promoting liquid-liquid phase separation, the RFP tag also facilitated fibril formation, as the tag-dependent liquid condensates rapidly underwent a liquid-to-solid transition. The rate of fibril formation under these conditions was significantly faster than that of the untagged protein. When expressed in cells, the RFP tagged Httex1 formed larger aggregates with different antibody staining patterns compared to untagged Httex1. Collectively, these data reveal that the addition of a fluorescent protein tag significantly impacts liquid and solid phase separations of Httex1 in vitro and leads to altered aggregation in cells. Considering that the tagged Httex1 is commonly used to study the mechanisms of Httex1 misfolding and toxicity, our findings highlight the importance to validate the conclusions with untagged protein.

Keywords:  Huntington’s disease; amyloid; fibril; huntingtin exon-1; liquid-liquid phase separation; polyglutamine; protein aggregation

DOI:  https://doi.org/10.1016/j.jbc.2023.105585
Proc Natl Acad Sci U S A. 2024 Jan 02. 121(1): e2312306120

Lysophagy protects against propagation of α-synuclein aggregation through ruptured lysosomal vesicles.

Keita Kakuda, Kensuke Ikenaka, Akiko Kuma, Junko Doi, César Aguirre, Nan Wang, Takahiro Ajiki, Chi-Jing Choong, Yasuyoshi Kimura, Shaymaa Mohamed Mohamed Badawy, Takayuki Shima, Shuhei Nakamura, Kousuke Baba, Seiichi Nagano, Yoshitaka Nagai, Tamotsu Yoshimori, Hideki Mochizuki.

  The neuron-to-neuron propagation of misfolded α-synuclein (αSyn) aggregates is thought to be key to the pathogenesis of synucleinopathies. Recent studies have shown that extracellular αSyn aggregates taken up by the endosomal-lysosomal system can rupture the lysosomal vesicular membrane; however, it remains unclear whether lysosomal rupture leads to the transmission of αSyn aggregation. Here, we applied cell-based αSyn propagation models to show that ruptured lysosomes are the pathway through which exogenous αSyn aggregates transmit aggregation, and furthermore, this process was prevented by lysophagy, i.e., selective autophagy of damaged lysosomes. αSyn aggregates accumulated predominantly in lysosomes, causing their rupture, and seeded the aggregation of endogenous αSyn, initially around damaged lysosomes. Exogenous αSyn aggregates induced the accumulation of LC3 on lysosomes. This LC3 accumulation was not observed in cells in which a key regulator of autophagy, RB1CC1/FIP200, was knocked out and was confirmed as lysophagy by transmission electron microscopy. Importantly, RB1CC1/FIP200-deficient cells treated with αSyn aggregates had increased numbers of ruptured lysosomes and enhanced propagation of αSyn aggregation. Furthermore, various types of lysosomal damage induced using lysosomotropic reagents, depletion of lysosomal enzymes, or more toxic species of αSyn fibrils also exacerbated the propagation of αSyn aggregation, and impaired lysophagy and lysosomal membrane damage synergistically enhanced propagation. These results indicate that lysophagy prevents exogenous αSyn aggregates from escaping the endosomal-lysosomal system and transmitting aggregation to endogenous cytosolic αSyn via ruptured lysosomal vesicles. Our findings suggest that the progression and severity of synucleinopathies are associated with damage to lysosomal membranes and impaired lysophagy.

Keywords:  lysophagy; lysosomal vesicle rupture; synucleinopathy; α-synuclein

DOI:  https://doi.org/10.1073/pnas.2312306120
Life Sci. 2023 Dec 21. pii: S0024-3205(23)00997-9. [Epub ahead of print] 122362

Morin suppresses mTORc1/IRE-1α/JNK and IP3R-VDAC-1 pathways: Crucial mechanisms in apoptosis and mitophagy inhibition in experimental Huntington's disease, supported by in silico molecular docking simulations.

Mohamed A El-Emam, Eman Sheta, Hanan S El-Abhar, Dalaal M Abdallah, Ahmed M El Kerdawy, Wagdy M Eldehna, Mennatallah A Gowayed.

  AIMS: Endoplasmic reticulum stress (ERS) with aberrant mitochondrial-ER contact (MERC), mitophagy, and apoptosis are interconnected determinants in neurodegenerative diseases. Previously, we proved the potential of Morin hydrate (MH), a potent antioxidant flavonoid, to mitigate Huntington's disease (HD)-3-nitropropionic acid (3-NP) model by modulating glutamate/calpain/Kidins220/BDNF trajectory. Extending our work, we aimed to evaluate its impact on combating the ERS/MERC, mitophagy, and apoptosis.METHODS: Rats were subjected to 3-NP for 14 days and post-treated with MH and/or the ERS inducer WAG-4S for 7 days. Disease progression was assessed by gross inspection and striatal biochemical, histopathological, immunohistochemical, and transmission electron microscopical (TEM) examinations. A molecular docking study was attained to explore MH binding to mTOR, JNK, the kinase domain of IRE1-α, and IP3R.
KEY FINDINGS: MH decreased weight loss and motor dysfunction using open field and rotarod tests. It halted HD degenerative striatal neurons and nucleus/mitochondria ultra-microscopic alterations reflecting neuroprotection. Mechanistically, MH deactivated striatal mTOR/IRE1-α/XBP1s&JNK/IP3R, PINK1/Ubiquitin/Mfn2, and cytochrome c/caspase-3 signaling pathways, besides enhancing p-PGC-1α and p-VDAC1. WAG-4S was able to ameliorate all effects initiated by MH to different extents. Molecular docking simulations revealed promising binding patterns of MH and hence its potential inhibition of the studied proteins, especially mTOR, IP3R, and JNK.
SIGNIFICANCE: MH alleviated HD-associated ERS, MERC, mitophagy, and apoptosis. This is mainly achieved by combating the mTOR/IRE1-α signaling, IP3R/VDAC hub, PINK1/Ubiquitin/Mfn2, and cytochrome c/caspase 3 axis to be worsened by WAG-4S. Molecular docking simulations showed the promising binding of MH to mTOR and JNK as novel identified targets.

Keywords:  3-Nitropropionic acid; ER stress; Huntington's disease; MH; Mitophagy; Neuronal apoptosis

DOI:  https://doi.org/10.1016/j.lfs.2023.122362
Redox Biol. 2023 Dec 18. pii: S2213-2317(23)00404-4. [Epub ahead of print]69 103003

NFE2L1/Nrf1 serves as a potential therapeutical target for neurodegenerative diseases.

Kamila Łuczyńska, Zhengwen Zhang, Tadeusz Pietras, Yiguo Zhang, Hiroaki Taniguchi.

  The failure of the proper protein turnover in the nervous system is mainly linked to a variety of neurodegenerative disorders. Therefore, a better understanding of key protein degradation through the ubiquitin-proteasome system is critical for effective prevention and treatment of those disorders. The proteasome expression is tightly regulated by a CNC (cap'n'collar) family of transcription factors, amongst which the nuclear factor-erythroid 2-like bZIP factor 1 (NFE2L1, also known as Nrf1, with its long isoform TCF11 and short isoform LCR-F1) has been identified as an indispensable regulator of the transcriptional expression of the ubiquitin-proteasome system. However, much less is known about how the pivotal role of NFE2L1/Nrf1, as compared to its homologous NFE2L2 (also called Nrf2), is translated to its physiological and pathophysiological functions in the nervous system insomuch as to yield its proper cytoprotective effects against neurodegenerative diseases. The potential of NFE2L1 to fulfill its unique neuronal function to serve as a novel therapeutic target for neurodegenerative diseases is explored by evaluating the hitherto established preclinical and clinical studies of Alzheimer's and Parkinson's diseases. In this review, we have also showcased a group of currently available activators of NFE2L1, along with an additional putative requirement of this CNC-bZIP factor for healthy longevity based on the experimental evidence obtained from its orthologous SKN1-A in Caenorhabditis elegans.

Keywords:  CNC; NFE2L1(Nrf1); NFE2L2(Nrf2); Neuroprotection; SKN-1; neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.redox.2023.103003
Curr Pharm Des. 2023 Dec 26.

Understanding the Therapeutic Approaches for Neuroprotection.

Nazrana Payal, Lalit Sharma, Aditi Sharma, Yahya Hosan Hobanii, Mashael Ahmed Hakami, Nemat Ali, Summya Rashid, Monika Sachdeva, Monica Gulati, Shivam Yadav, Sridevi Chigurupati, Abhiav Singh, Haroon Khan, Tapan Behl.

  The term "neurodegenerative disorders" refers to a group of illnesses in which deterioration of nerve structure and function is a prominent feature. Cognitive capacities such as memory and decision-making deteriorate as a result of neuronal damage. The primary difficulty that remains is safeguarding neurons since they do not proliferate or regenerate spontaneously and are therefore not substituted by the body after they have been damaged. Millions of individuals throughout the world suffer from neurodegenerative diseases. Various pathways lead to neurodegeneration, including endoplasmic reticulum stress, calcium ion overload, mitochondrial dysfunction, reactive oxygen species generation, and apoptosis. Although different treatments and therapies are available for neuroprotection after a brain injury or damage, the obstacles are inextricably connected. Several studies have revealed the pathogenic effects of hypothermia, different breathed gases, stem cell treatments, mitochondrial transplantation, multi-pharmacological therapy, and other therapies that have improved neurological recovery and survival outcomes after brain damage. The present review highlights the use of therapeutic approaches that can be targeted to develop and understand significant therapies for treating neurodegenerative diseases.

Keywords:  Neurodegenerative diseases; brain injury/damage; drug targeting; neurodegeneration; oxidative stress; therapeutics.

DOI:  https://doi.org/10.2174/0113816128275761231103102125