bims-proned 2024-11-10 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024‒11‒10
fiveteen papers selected by
Verena Kohler, Umeå University

Recent pharmacological insights on abating toxic protein species burden in neurological disorders: Emphasis on 26S proteasome activation.
Liquid-liquid phase separation and conformational strains of α-Synuclein: implications for Parkinson's disease pathogenesis.
Analysis of mitochondrial protein aggregation and disaggregation.
Serine phosphorylation mimics of Aβ form distinct, non-cross-seeding fibril morphs.
The potential of natural products to inhibit abnormal aggregation of α-Synuclein in the treatment of Parkinson's disease.
Molecular mechanisms at the basis of the protective effect exerted by EPPS on neurodegeneration induced by prefibrillar amyloid oligomers.
Exploring the Impact of Physiological C-Terminal Truncation on α-Synuclein Conformations to Unveil Mechanisms Regulating Pathological Aggregation.
Threonine-rich carboxyl-terminal extension drives aggregation of stalled polypeptides.
Novel Piperazine Based Compounds Target Alzheimer's Disease Relevant Amyloid β42 and Tau Derived Peptide AcPHF6, and the Lead Molecule Increases Viability in the Flies Expressing Human Tau Protein.
USP14 inhibition enhances Parkin-independent mitophagy in iNeurons.
GSK-3β inhibitor amplifies autophagy-lysosomal pathways by regulating TFEB in Parkinson's disease models.
Fluorescence Detection and Inhibition Mechanisms of DNTPH on Aβ42 Oligomers Characterized as Products in the Four Stages of Aggregation.
14-3-3 protein and its isoforms: A common diagnostic marker for Alzheimer's disease, Parkinson's disease and glaucomatous neurodegeneration.
Early α-synuclein/synapsin III co-accumulation, nigrostriatal dopaminergic synaptopathy and denervation in the MPTPp mouse model of Parkinson's Disease.
TREM2 signaling in Parkinson's disease: Regulation of microglial function and α-synuclein pathology.

Life Sci. 2024 Nov 01. pii: S0024-3205(24)00796-3. [Epub ahead of print]359 123206

Recent pharmacological insights on abating toxic protein species burden in neurological disorders: Emphasis on 26S proteasome activation.

Mahmoud A Desouky, Haidy E Michel, Doaa A Elsherbiny, Mina Y George.

  Protein homeostasis (proteostasis) refers to the plethora of mechanisms that safeguard the proper folding of the newly synthesized proteins. It entails various intricately regulated cues that demolish the toxic protein species to prevent their aggregation. The ubiquitin-proteasome system (UPS) is recognized as a salient protein degradation system, with a substantial role in maintaining proteostasis. However, under certain circumstances the protein degradation capacity of the UPS is overwhelmed, leading to the accumulation of misfolded proteins. Several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington disease, and amyotrophic lateral sclerosis are characterized with the presence of protein aggregates and proteinopathy. Accordingly, enhancing the 26S proteasome degradation activity might delineate a pioneering approach in targeting various proteotoxic disorders. Regrettably, the exact molecular approaches that enhance the proteasomal activity are still not fully understood. Therefore, this review aimed to underscore several signaling cascades that might restore the degradation capacity of this molecular machine. In this review, we discuss the different molecular components of the UPS and how 26S proteasomes are deleteriously affected in many neurodegenerative diseases. Moreover, we summarize different signaling pathways that can be utilized to renovate the 26S proteasome functional capacity, alongside currently known druggable targets in this circuit and various classes of proteasome activators.

Keywords:  Neurological disorders; Proteasome activation; Proteostasis; Proteotoxic disorders; Ubiquitin-proteasome system

DOI:  https://doi.org/10.1016/j.lfs.2024.123206
Front Mol Neurosci. 2024 ;17 1494218

Liquid-liquid phase separation and conformational strains of α-Synuclein: implications for Parkinson's disease pathogenesis.

Eva D Ruiz-Ortega, Anna Wilkaniec, Agata Adamczyk.

  Parkinson's disease (PD) and other synucleinopathies are characterized by the aggregation and deposition of alpha-synuclein (α-syn) in brain cells, forming insoluble inclusions such as Lewy bodies (LBs) and Lewy neurites (LNs). The aggregation of α-syn is a complex process involving the structural conversion from its native random coil to well-defined secondary structures rich in β-sheets, forming amyloid-like fibrils. Evidence suggests that intermediate species of α-syn aggregates formed during this conversion are responsible for cell death. However, the molecular events involved in α-syn aggregation and its relationship with disease onset and progression remain not fully elucidated. Additionally, the clinical and pathological heterogeneity observed in various synucleinopathies has been highlighted. Liquid-liquid phase separation (LLPS) and condensate formation have been proposed as alternative mechanisms that could underpin α-syn pathology and contribute to the heterogeneity seen in synucleinopathies. This review focuses on the role of the cellular environment in α-syn conformational rearrangement, which may lead to pathology and the existence of different α-syn conformational strains with varying toxicity patterns. The discussion will include cellular stress, abnormal LLPS formation, and the potential role of LLPS in α-syn pathology.

Keywords:  Parkinson’s disease; alpha-synuclein; cellular stress; conformational strains; liquid–liquid phase separation; mitochondria; protein aggregation

DOI:  https://doi.org/10.3389/fnmol.2024.1494218
Methods Enzymol. 2024 ;pii: S0076-6879(24)00388-4. [Epub ahead of print]707 475-498

Analysis of mitochondrial protein aggregation and disaggregation.

Wolfgang Voos, Anne Wilkening, Robin Ostermann, Michael Bruderek, Witold Jaworek, Laura Ruland.

  Deficits of mitochondrial functions have been identified in many human pathologies, in particular in age-related human neurodegenerative diseases. Hence, the molecular causes for mitochondrial dysfunction and potential protection mechanisms have become a major topic in modern cell biology. Apart from defects in their structural integrity, problems in mitochondrial protein biogenesis, including polypeptide transport, folding and assembly to active enzymes, all may result in some degree of functional defects of the organelle. An accumulation of misfolded polypeptides inside mitochondria, confounded by the dual source of mitochondrial polypeptides, will result in the formation of protein aggregates. Such aggregate accumulation bears a cell-toxic potential, resulting in mitochondrial and correlated cellular damages, summarized in the term "aggregate proteotoxicity". Here, we discuss methods to analyze protein aggregation in the mitochondrial matrix compartment. We also address techniques to characterize the biochemical mechanisms that reduce aggregate proteotoxicity, the disaggregation or resolubilization of aggregated polypeptides and the sequestration and neutralization of mitochondrial aggregates at specific sites inside a cell.

Keywords:  ATP-dependent proteases; Human cells; Mitochondria; Molecular chaperones; Protein aggregation; Proteotoxicity; Yeast

DOI:  https://doi.org/10.1016/bs.mie.2024.07.048
Chem Sci. 2024 Oct 11.

Serine phosphorylation mimics of Aβ form distinct, non-cross-seeding fibril morphs.

Kalyani Sanagavarapu, Georg Meisl, Veronica Lattanzi, Katja Bernfur, Birgitta Frohm, Ulf Olsson, Tuomas P J Knowles, Anders Malmendal, Sara Linse.

The self-assembly of amyloid-β peptide (Aβ) into fibrils and oligomers is linked to Alzheimer's disease (AD). Fibrillar aggregates in AD patient's brains contain several post-translational modifications, including phosphorylation at positions 8 and 26. These play a key role in modifying the aggregation propensity of Aβ, yet how they affect the mechanism of aggregation is only poorly understood. Here we elucidate the aggregation mechanism of Aβ42 peptides with phosphomimic mutations at these positions, with glutamine mimicking the size, and glutamate mimicking both the size and charge effect. We find that all variants are less aggregation-prone than wild-type Aβ42 with the glutamate mutants showing the largest reduction. Secondary nucleation is the dominant nucleation route for all variants, as confirmed using seeding experiments; however, its rate is reduced by about an order of magnitude or more for all variants relative to wild-type. S26Q and S26E fibrils fail to catalyse nucleation of wild-type monomers and vice versa, while the S8 variants co-aggregate more readily with wild-type. Ultrastructural analyses by cryo-electron microscopy and small angle X-ray scattering reveal an altered structure with longer node-to-node distance and smaller cross-section dimensions of S26Q fibrils. These results imply that structural compatibility between fibrils and monomer is a key determinant in secondary nucleation, and that small modifications can alter the preferred fibril structure, and thus its potential to induce aggregation of other variants. Overall, our results indicate that phosphorylation could play a key role in controlling aggregation propensity and may lead to the formation of distinct, non-cross-seeding fibril populations.

DOI: https://doi.org/10.1039/d3sc06343g
Front Pharmacol. 2024 ;15 1468850

The potential of natural products to inhibit abnormal aggregation of α-Synuclein in the treatment of Parkinson's disease.

Kaixia Yang, Zhongyue Lv, Wen Zhao, Guogang Lai, Cheng Zheng, Feiteng Qi, Cui Zhao, Kaikai Hu, Xiao Chen, Fan Fu, Jiayi Li, Guomin Xie, Haifeng Wang, Xiping Wu, Wu Zheng.

  Parkinson's disease (PD), as a refractory neurological disorder with complex etiology, currently lacks effective therapeutic agents. Natural products (NPs), derived from plants, animals, or microbes, have shown promising effects in PD models through their antioxidative and anti-inflammatory properties, as well as the enhancement of mitochondrial homeostasis and autophagy. The misfolding and deposition of α-Synuclein (α-Syn), due to abnormal overproduction and impaired clearance, being central to the death of dopamine (DA) neurons. Thus, inhibiting α-Syn misfolding and aggregation has become a critical focus in PD discovery. This review highlights NPs that can reduce α-Syn aggregation by preventing its overproduction and misfolding, emphasizing their potential as novel drugs or adjunctive therapies for PD treatment, thereby providing further insights for clinical translation.

Keywords:  Parkinson’s disease; aggregation; misfolding; natural products; α-Synuclein

DOI:  https://doi.org/10.3389/fphar.2024.1468850
Sci Rep. 2024 11 03. 14(1): 26533

Molecular mechanisms at the basis of the protective effect exerted by EPPS on neurodegeneration induced by prefibrillar amyloid oligomers.

Beatrice Zarrilli, Roberto Bonanni, Marcello Belfiore, Mariagrazia Severino, Ida Cariati, Raoul Fioravanti, Giacomo Cappella, Simona Sennato, Claudio Frank, Cristiano Giordani, Virginia Tancredi, Cecilia Bombelli, Marco Diociaiuti, Giovanna D'Arcangelo.

  It has been shown recently, without an explanation of the possible molecular mechanisms involved, that 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic (EPPS) acid effectively protects from the neurotoxicity induced by oligomers and plaques formed by the protein amyloid-β protein. Here we report the same protective effect, obtained in vitro (HT22-diff cell line) and ex vivo (hippocampal slices) models, against amyloid neurotoxicity induced by oligomers of salmon Calcitonin (sCT), which has been shown to be a good model for the study of neurodegenerative diseases. Based on biophysical studies focusing on the protein aggregation kinetic and the interaction of the aggregates with model membranes, we propose a possible molecular mechanism underlying the protective effects. Taken together, our results indicate that EPPS is able to counteract the direct association (primary aggregation) of harmless low-molecular weight aggregates (dimers and trimers) or their aggregation catalysed by surfaces present in the solution (secondary aggregation). Thus, EPPS stabilizes harmless aggregates and hinders the formation of toxic and metastable prefibrillar oligomers. Overall, our data demonstrate that EPPS is an excellent drug candidate for the treatment of neurodegeneration due to misfolded proteins, such as Alzheimer's or Parkinson's disease.

Keywords:  4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS); Alzheimer’s disease (AD); Prefibrillar Oligomers (PFOs); neurodegeneration; salmon calcitonin (sCT)

DOI:  https://doi.org/10.1038/s41598-024-77859-9
J Chem Inf Model. 2024 Nov 06.

Exploring the Impact of Physiological C-Terminal Truncation on α-Synuclein Conformations to Unveil Mechanisms Regulating Pathological Aggregation.

Fengjuan Huang, Jiajia Yan, Huan Xu, Ying Wang, Xiaohan Zhang, Yu Zou, Jiangfang Lian, Feng Ding, Yunxiang Sun.

Emerging evidence suggests that physiological C-terminal truncation of α-synuclein (αS) plays a critical role in regulating liquid-liquid phase separation and promoting amyloid aggregation, processes implicated in neurodegenerative diseases such as Parkinson's disease (PD). However, the molecular mechanisms through which C-terminal truncation influences αS conformation and modulates its aggregation remain poorly understood. In this study, we investigated the impact of C-terminal truncation on αS conformational dynamics by comparing full-length αS1-140 with truncated αS1-103 monomers using atomistic discrete molecular dynamics simulations. Our findings revealed that both αS1-140 and αS1-103 primarily adopted helical conformations around residues 7-32, while residues 36-95, located in the second half of the N-terminal and NAC domains, predominantly formed a dynamic β-sheet core. The C-terminus of αS1-140 was largely unstructured and dynamically wrapped around the β-sheet core. While residues 1-95 exhibited similar secondary structure propensities in both αS1-140 and αS1-103, the dynamic capping by the C-terminus in αS1-140 slightly enhanced β-sheet formation around residues 36-95. In contrast, key aggregation-driving regions (residues 2-9, 36-42, 45-57, and 68-78) were dynamically shielded by the C-terminus in αS1-140, reducing their exposure and potentially preventing interpeptide interactions that drive aggregation. C-terminal truncation, on the other hand, increased the exposed surface area of these aggregation-prone regions, thereby enhancing interpeptide interactions, phase separation, and amyloid aggregation. Overall, our simulations provide valuable insights into the conformational effects of C-terminal truncation on αS and its role in promoting pathological aggregation.

DOI: https://doi.org/10.1021/acs.jcim.4c01839
Mol Cell. 2024 Nov 01. pii: S1097-2765(24)00834-7. [Epub ahead of print]

Threonine-rich carboxyl-terminal extension drives aggregation of stalled polypeptides.

Weili Denyse Chang, Mi-Jeong Yoon, Kian Hua Yeo, Young-Jun Choe.

  Ribosomes translating damaged mRNAs may stall and prematurely split into their large and small subunits. The split large ribosome subunits can continue elongating stalled polypeptides. In yeast, this mRNA-independent translation appends the C-terminal alanine/threonine tail (CAT tail) to stalled polypeptides. If not degraded by the ribosome-associated quality control (RQC), CAT-tailed stalled polypeptides form aggregates. How the CAT tail, a low-complexity region composed of alanine and threonine, drives protein aggregation remains unknown. In this study, we demonstrate that C-terminal polythreonine or threonine-enriched tails form detergent-resistant aggregates. These aggregates exhibit a robust seeding effect on shorter tails with lower threonine content, elucidating how heterogeneous CAT tails co-aggregate. Polythreonine aggregates sequester molecular chaperones, disturbing proteostasis and provoking the heat shock response. Furthermore, polythreonine cross-seeds detergent-resistant polyserine aggregation, indicating structural similarity between the two aggregates. This study identifies polythreonine and polyserine as a distinct group of aggregation-prone protein motifs.

Keywords:  CAT tail; RQC; chaperone; heat shock response; molecular chaperone; polyQ; polyserine; polyserine aggregation; polythreonine; polythreonine aggregation; proteostasis; ribosome stalling

DOI:  https://doi.org/10.1016/j.molcel.2024.10.011
ACS Chem Neurosci. 2024 Nov 06. 15(21): 3901-3914

Novel Piperazine Based Compounds Target Alzheimer's Disease Relevant Amyloid β42 and Tau Derived Peptide AcPHF6, and the Lead Molecule Increases Viability in the Flies Expressing Human Tau Protein.

Christopher Armstrong, Dan Luo, Anna Gretzinger, Deepti Pandey, Andrew Lipchik, Sokol V Todi, Aloke K Dutta.

  Alzheimer's disease (AD) is the leading form of dementia in the United States and the world. The pathophysiology of AD is complex and multifaceted. Accumulation of senile plaques and neurofibrillary tangles (NFTs) are hallmarks of AD. The aggregation of amyloid β (senile plaques) and tau tangles (NFTs) results in the death of neurons in the cortex and hippocampus, which manifests itself in cognitive decline and memory loss. Current therapies rely on conventional approaches that have only treated the underlying symptoms without disease modification. Data from clinical studies point to a complex role of amyloid β (Aβ) in a way that enhances the tau phenotype throughout the disease process. To address the co-pathogenic role of Aβ and tau, we undertook development of multitarget compounds aiming at both tau and Aβ to slow or stop disease progression and provide neuroprotection. Here, we demonstrate a dose-dependent effect of the novel test compounds that inhibit aggregation of AcPHF6 (a shorter version of tau protein) and Aβ1-42 peptides in thioflavin T fluorescent assays. The compounds were also shown to disaggregate preformed aggregates dose dependently. To further validate these findings, circular dichroism experiments were carried out to examine the nature of inhibition. Additionally, transmission electron microscopy experiments were carried out to gain insights into the morphologies of aggregates obtained from dose-dependent inhibition of AcPHF6 and Aβ1-42 as well as dissociation of preformed aggregates from these peptides. Compounds D-687 and D-688 reversed Aβ1-42 induced toxicity in SH-SH5Y cells, significantly demonstrating neuroprotective properties. Finally, in a study with Drosophila melanogaster expressing human tau protein isoform (2N4R) in all the neurons, compound D-688 significantly increased the survival of flies compared to vehicle treated controls. Future studies will further examine the neuroprotective properties of these lead compounds in various animal models.

Keywords:  Alzheimer’s disease; Drosophila fly; amyloid precursor protein; amyloid βeta; neurofibrillary tangles; polyphenol; tau protein; transmission electron microscopy

DOI:  https://doi.org/10.1021/acschemneuro.4c00220
Pharmacol Res. 2024 Oct 30. pii: S1043-6618(24)00429-8. [Epub ahead of print] 107484

USP14 inhibition enhances Parkin-independent mitophagy in iNeurons.

Bernardo Greta, A Prado Miguel, Dashtmian Anna Roshani, Mariavittoria Favaro, Sofia Mauri, Alice Borsetto, Elena Marchesan, Joao A Paulo, Steve P Gygi, Daniel J Finley, Elena Ziviani.

  Loss of proteostasis is well documented during physiological aging and depends on the progressive decline in the activity of two major degradative mechanisms: the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway. This decline in proteostasis is exacerbated in age-associated neurodegenerative diseases, such as Parkinson's Disease (PD). In PD, patients develop an accumulation of aggregated proteins and dysfunctional mitochondria, which leads to ROS production, neuroinflammation and neurodegeneration. We recently reported that inhibition of the deubiquitinating enzyme USP14, which is known to enhance both the UPS and autophagy, increases lifespan and rescues the pathological phenotype of two Drosophila models of PD. Studies on the effects of USP14 inhibition in mammalian neurons have not yet been conducted. To close this gap, we exploited iNeurons differentiated from human embryonic stem cells (hESCs), and investigated the effect of inhibiting USP14 in these cultured neurons. Quantitative global proteomics analysis performed following genetic ablation or pharmacological inhibition of USP14 demonstrated that USP14 loss of function specifically promotes mitochondrial autophagy in iNeurons. Biochemical and imaging data also showed that USP14 inhibition enhances mitophagy. The mitophagic effect of USP14 inhibition proved to be PINK1/Parkin- independent, instead relying on expression of the mitochondrial E3 Ubiquitin Ligase MITOL/MARCH5. Notably, USP14 inhibition normalized the mitochondrial defects of Parkin KO human neurons.

Keywords:  Autophagy; MARCH5/MITOL; Mitophagy; PINK1; Parkin; UPS; USP14

DOI:  https://doi.org/10.1016/j.phrs.2024.107484
Exp Neurol. 2024 Oct 25. pii: S0014-4886(24)00359-5. [Epub ahead of print] 115033

GSK-3β inhibitor amplifies autophagy-lysosomal pathways by regulating TFEB in Parkinson's disease models.

Jiahong Zhong, Xihui Yu, Yunming Zhong, Liya Tan, Fayou Yang, Jialan Xu, Jianlin Wu, Zhuomiao Lin.

  Parkinson's disease (PD), a common neurodegenerative disorder characterized by degeneration of the substantia nigra and a marked increase in Lewy bodies in the brain, primarily manifests as motor dysfunction. Glycogen synthase kinase-3 beta (GSK-3β) is known to play a critical role in various pathological processes of neurodegenerative diseases. However, the impact of GSK-3β inhibitors on PD progression and the underlying molecular mechanisms responsible for the effects have not been fully elucidated. Using in vitro and mouse models of 1-methyl-4-phenylpyridine (MPP+)-or methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD, we found that inhibition of GSK-3β activity alleviated mitochondrial damage, cell apoptosis, and neuronal cell loss by promoting the nuclear translocation of transcription factor EB (TFEB), thereby amplifying the autophagy-lysosomal pathway (ALP). Importantly, siRNA silencing of the TFEB gene impaired the GSK-3β inhibitor-mediated activation of the ALP pathway, thus negating the metabolic support required for neuronal functional improvement. Short-term treatment with the GSK-3β inhibitor significantly ameliorated motor dysfunction and improved motor coordination in model mice with MPTP-induced PD. GSK-3β inhibition increased the ALP and TFEB activities in the mice, thereby reducing α-synuclein aggregation and neuronal damage. In conclusion, our study demonstrates that inhibition of GSK-3β activity can delay the pathological processes of PD via promotion of the TFEB-ALP pathway, potentially providing a novel therapeutic target for this neurodegenerative disorder.

Keywords:  Autophagy-lysosomal pathway; GSK-3β inhibitor; MPP(+); Parkinson's disease; TFEB

DOI:  https://doi.org/10.1016/j.expneurol.2024.115033
ACS Chem Neurosci. 2024 Nov 04.

Fluorescence Detection and Inhibition Mechanisms of DNTPH on Aβ42 Oligomers Characterized as Products in the Four Stages of Aggregation.

Mengke Jia, Ye Li, Chuanbo Wang, Xvzhi Gao, Yvning Guan, Hongqi Ai.

  Aβ42 aggregation was implicated in the pathogenesis of Alzheimer's disease (AD) without effective treatment available currently. Future efforts in clinical trials should instead focus on applying those antiamyloid treatment strategies to the preclinical stage and "the earlier, the better". How to identify and inhibit Aβ42 oligomers in the different stages of aggregation is therefore becoming the key to controlling primary aggregation and consequent AD development. Aggregation-induced emission probe DNTPH was demonstrated recently, enabling detection of amyloid at wavelengths up to 710 nm and exhibiting strong inhibitory effects on Aβ fibrosis at low dose. However, the detection and inhibition mechanisms of Aβ oligomers at various early stages of aggregation remain unknown. To this end, we built four different morphologies of Aβ42 pentamers characterized by products in monomeric aggregate (PM), primary nucleation (PP), secondary nucleation (PS), and fibril stages (PF) to explore the distinguishable ability and inhibition mechanisms of DNTPH with different concentrations upon binding. The results showcased that DNTPH does detect the four different Aβ42 oligomers with conspicuous fluorescence (λPM = 657 nm, λPP = 639 nm, λPS = 630 nm, and λPF = 648 nm) but fails to distinguish them, indicating that additional improvements are required further for the probe to achieve it. The inhibition mechanisms of DNTPH on the four Aβ42 aggregation are however of amazing differences. For PM and PP, aggregation was inhibited by altering the secondary structural composition, i.e., by decreasing the β-sheet and toxic turn (residues 22-23) probabilities, respectively. For PS, inhibition was achieved by segregating and keeping the two disordered monomeric species (PSM) away from the ordered secondary seed species (PSF) and consequently blocking further growth of the PSF seed. The inhibition mechanism for PS is first probed and proposed so far, as far as we know, and the corresponding aggregation stage of PS is the most important one among the four stages. The inhibition of PF was triggered by distorting the fibril chains, disrupting the ordered fibril surface for the contact of monomers. In addition, the optimal inhibitory concentrations of DNTPH for PM, PP, and PF were determined to be 1:3, while for PS, it was 1:5. This outcome offers a novel perspective for designing drugs targeting Aβ42 oligomers at different aggregation stages.

Keywords:  Aβ42 oligomers; DNTPH detection; four aggregation stages; inhibition mechanisms

DOI:  https://doi.org/10.1021/acschemneuro.4c00509
Ageing Res Rev. 2024 Nov 01. pii: S1568-1637(24)00390-8. [Epub ahead of print]102 102572

14-3-3 protein and its isoforms: A common diagnostic marker for Alzheimer's disease, Parkinson's disease and glaucomatous neurodegeneration.

Siva Prasad Panda, Adarsh Kesharwani, Bhoopendra Singh, Arya Lakshmi Marisetti, Mvnl Chaitanya, Saurabh Dahiya, S Ponnusankar, Sanjesh Kumar, Mansi Singh, Praveen Kumar Shakya, P Dharani Prasad, Ajay Guru.

  There is a molecular coupling between neurodegenerative diseases, including glaucomatous neurodegeneration (GN), Alzheimer's disease (AD), and Parkinson's disease (PD). Many cells in the eye and the brain have the right amount of 14-3-3 proteins (14-3-3 s) and their isoforms, such as β, ε, γ, η, θ, π, and γ. These cells include keratocytes, endothelial cells, corneal epithelial cells, and primary conjunctival epithelial cells. 14-3-3 s regulate autophagy and mitophagy, help break down built-up proteins, and connect to other proteins to safeguard against neurodegeneration in AD, PD, GN, and glioblastoma. By interacting with these proteins, 14-3-3 s stop Bad and Bax proteins from entering mitochondria and make them less effective. These interactions inhibit neuronal apoptosis. They play many important roles in managing the breakdown of lysosomal proteins, tau, and Aβ, which is why the 14-3-3 s could be used as therapeutic targets in AD. Furthermore, researchers have discovered 14-3-3 s in Lewy bodies, which are associated with various proteins like LRRK2, ASN, and Parkin, all of which play a role in developing Parkinson's disease (PD). The 14-3-3 s influence the premature aging and natural wrinkles of human skin. Studies have shown that lowering 14-3-3 s in the brain can lead to an increase in cell-death proteins like BAX and ERK, which in turn causes excitotoxicity-induced neurodegeneration. This review aimed to clarify the role of 14-3-3 s in the neuropathology of AD, PD, and GN, as well as potential diagnostic markers for improving neuronal survival and repair.

Keywords:  14–3–3 s; Alzheimer’s disease; Glaucomatous neurodegeneration; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.arr.2024.102572
Exp Neurol. 2024 Nov 03. pii: S0014-4886(24)00366-2. [Epub ahead of print]383 115040

Early α-synuclein/synapsin III co-accumulation, nigrostriatal dopaminergic synaptopathy and denervation in the MPTPp mouse model of Parkinson's Disease.

Marcello Serra, Gaia Faustini, Viviana Brembati, Maria Antonietta Casu, Marina Pizzi, Micaela Morelli, Annalisa Pinna, Arianna Bellucci.

  Parkinson's disease (PD) is characterized by the loss of nigrostriatal dopaminergic neurons and the presence of Lewy bodies (LB), intraneuronal inclusions mainly composed of α-synuclein (α-Syn) fibrils. Compelling evidence supports that, in PD brains, synapses are the sites where neurodegeneration initiates several years before the manifestation of motor symptoms. Furthermore, the amount of α-Syn deposited at synaptic terminals is several orders greater than that constituting LB. This hints that pathological synaptic α-Syn aggregates may be the main trigger for the retrograde synapse-to-cell body degeneration pattern characterizing early prodromal phases of PD. Identifying reliable biomarkers of synaptopathy is therefore crucial for early diagnosis. Here, we studied the alterations of key dopaminergic and non-dopaminergic striatal synaptic markers during the initial phases of axonal and cell body degeneration in mice subjected to 3 or 10 administrations of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine + probenecid (MPTPp), a model for early prodromal PD. We found that MPTPp administration resulted in progressive deposition of α-Syn, advancing from synaptic terminals to axons and dopaminergic neuron cell bodies. This was accompanied by marked co-accumulation of Synapsin III (Syn III), a synaptic protein previously identified as a component of α-Syn fibrils in post-mortem PD brains and as a main stabilizer of α-Syn aggregates, as well as very early and severe reduction of vesicular monoamine transporter 2 (VMAT2), dopamine transporter (DAT) and tyrosine hydroxylase (TH) immunoreactivity in nigrostriatal neurons. Results also showed that striatal α-Syn accumulation and VMAT2 decrease, unlike other markers, did not recover following washout from 10 MPTPp administrations, supporting that these changes were precocious and severe. Finally, we found that early changes in striatal α-Syn, Syn III, VMAT2 and DAT observed following 3 MPTPp administrations, correlated with nigrostriatal neuron loss after 10 MPTPp administrations. These findings indicate that α-Syn/Syn III co-deposition characterizes very early stages of striatal dopaminergic dysfunction in the MPTPp model and highlight that VMAT2 and Syn III could be two reliable molecular imaging biomarkers to predict dopamine neuron denervation and estimate α-Syn-related synaptopathy in prodromal and early symptomatic phases of PD.

Keywords:  Dopamine transporter; MPTPp; Parkinson's disease; Synapsin III; Tyrosine hydroxylase; Vesicular monoamine transporter 2; α-Synuclein

DOI:  https://doi.org/10.1016/j.expneurol.2024.115040
Int Immunopharmacol. 2024 Oct 26. pii: S1567-5769(24)01968-4. [Epub ahead of print]143(Pt 2): 113446

TREM2 signaling in Parkinson's disease: Regulation of microglial function and α-synuclein pathology.

Sijia Yin, Xiaosa Chi, Fang Wan, Yunna Li, Qiulu Zhou, Liang Kou, Yadi Sun, Jiawei Wu, Wenkai Zou, Yiming Wang, Zongjie Jin, Jinsha Huang, Nian Xiong, Yun Xia, Tao Wang.

  BACKGROUND: Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons, abnormal accumulation of α-synuclein (α-syn), and microglial activation. Triggering receptor expressed on myeloid cells 2 (TREM2) regulates multiple functions of microglia in the brain, and several studies have shown that TREM2 variant R47H is a risk factor for PD. However, the regulation of microglia by TREM2 in PD remains poorly understood.METHODS: We constructed PD cell and animal models using α-syn preformed fibrils. siRNA knockdown and lentiviral overexpression were used to perturb TREM2 levels in cells, and TREM2 knockout mice and lentiviral overexpression was used in animal models to investigate the effects of TREM2 on microglial function, α-syn-related pathology, and dopaminergic neuron degeneration.
RESULTS: Microglia phagocytosed α-syn preformed fibrils in a concentration- and time-dependent manner, with some capacity to degrade α-syn aggregates. TREM2 expression increased in PD. In the context of PD, TREM2 knockout mice exhibited worsened pathological α-syn spread, decreased microglial reactivity, and increased loss of TH-positive neurons in the substantia nigra compared to wild-type mice. TREM2 overexpression enhanced reactive microglial aggregation towards the pathological site. Cellular experiments revealed that reduced TREM2 impaired microglial phagocytosis and proliferation, but enhanced autophagy via the PI3K/AKT/mTOR pathway.
CONCLUSION: TREM2 signaling in PD maintains microglial phagocytosis, proliferation, and reactivity, stabilizing autophagy and proliferation via the PI3K/AKT/mTOR pathway. Regulating TREM2 levels may be beneficial in PD treatment.

Keywords:  Alpha-synuclein; Microglia; PI3K-AKT-mTOR pathway; Parkinson’s disease; TREM2

DOI:  https://doi.org/10.1016/j.intimp.2024.113446