bims-proned 2023-10-29 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2023–10–29
twenty papers selected by
Verena Kohler, Umeå University

Autophagy in Parkinson's Disease.
Pirh2 modulates amyloid-β aggregation through the regulation of glucose-regulated protein 78 and chaperone-mediated signaling.
Anionic Nanoplastic Contaminants Promote Parkinson's Disease-Associated α-Synuclein Aggregation.
Interaction of Proteins Involved in Neuronal Proteinopathies.
The Toxicities of A30P and A53T α-Synuclein Fibrils Can be Uniquely Altered by The Length and Saturation of Fatty Acids in Phosphatidylserine.
Opportunities for Cellular Rejuvenation in Alzheimer's Disease: How Epigenetic Reprogramming and Chaperone-Mediated Autophagy Are Enabling Next Generation Therapeutic Approaches.
Targeting GM2 Ganglioside Accumulation in Dementia: Current Therapeutic Approaches and Future Directions.
Adenosine Triphosphate (ATP) and Protein Aggregation in Age-Related Vision-Threatening Ocular Diseases.
The Effects of Lipids on α-Synuclein Aggregation In Vitro.
Nontoxic Aggregation-Induced Emissive Luminogen for the Detection of Amyloid Fibrils and Cellular Protein Aggregates.
Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend C. elegans Life- and Healthspan.
Tau accumulation in degradative organelles is associated to lysosomal stress.
Saturation mutagenesis of α-synuclein reveals monomer fold that modulates aggregation.
Localized synthesis of molecular chaperones sustains neuronal proteostasis.
Butyrylcholinesterase signal sequence self-aggregates and enhances amyloid fibril formation in vitro.
Understanding the Molecular Mechanisms of Polyphenol Inhibition of Amyloid β Aggregation.
A short peptide protects from age-onset proteotoxicity.
Retromer stabilization using a pharmacological chaperone protects in an α-synuclein based mouse model of Parkinson's.
Nascent Aβ42 fibrillization in synaptic endosomes precedes plaque formation in a mouse model of Alzheimer's like β-amyloidosis.
A New Role for RNA G-quadruplexes in Aging and Alzheimer's Disease.

Biomolecules. 2023 Sep 22. pii: 1435. [Epub ahead of print]13(10):

Autophagy in Parkinson's Disease.

Lior Nechushtai, Dan Frenkel, Ronit Pinkas-Kramarski.

  Parkinson's disease (PD) is a devastating disease associated with accumulation of α-synuclein (α-Syn) within dopaminergic neurons, leading to neuronal death. PD is characterized by both motor and non-motor clinical symptoms. Several studies indicate that autophagy, an important intracellular degradation pathway, may be involved in different neurodegenerative diseases including PD. The autophagic process mediates the degradation of protein aggregates, damaged and unneeded proteins, and organelles, allowing their clearance, and thereby maintaining cell homeostasis. Impaired autophagy may cause the accumulation of abnormal proteins. Incomplete or impaired autophagy may explain the neurotoxic accumulation of protein aggregates in several neurodegenerative diseases including PD. Indeed, studies have suggested the contribution of impaired autophagy to α-Syn accumulation, the death of dopaminergic neurons, and neuroinflammation. In this review, we summarize the recent literature on the involvement of autophagy in PD pathogenesis.

Keywords:  Parkinson’s disease (PD); apolipoprotein E4 (apoE4); autophagy; endocytosis; lysosomal degradation; synuclein α

DOI:  https://doi.org/10.3390/biom13101435
J Cell Physiol. 2023 Oct 26.

Pirh2 modulates amyloid-β aggregation through the regulation of glucose-regulated protein 78 and chaperone-mediated signaling.

Abhishek Singh, Shubhangini Tiwari, Sarika Singh.

  Amyloid-β (Aβ) protein aggregation in the brain is a pathological hallmark of Alzheimer's disease (AD) however, the underlying molecular mechanisms regulating amyloid aggregation are not well understood. Here, we studied the propitious role of E3 ubiquitin ligase Pirh2 in Aβ protein aggregation in view of its regulatory ligase activity in the ubiquitin-proteasome system employing both cellular and sporadic rodent models of AD. Pirh2 protein abundance was significantly increased during Streptozotocin (STZ) induced AD conditions, and transient silencing of Pirh2 significantly inhibited the Aβ aggregation and modified the dendrite morphology along with the substantial decrease in choline level in the differentiated neurons. MALDI-TOF/TOF, coimmunoprecipitation, and UbcH7-linked in vitro ubiquitylation analysis confirmed the high interaction of Pirh2 with chaperone GRP78. Furthermore, Pirh2 silencing inhibits the STZ induced altered level of endoplasmic reticulum stress and intracellular Ca2+ levels in neuronal N2a cells. Pirh2 silencing also inhibited the AD conditions related to the altered protein abundance of HSP90 and its co-chaperones which may collectively involve in the reduced burden of amyloid aggregates in neuronal cells. Pirh2 silencing further stabilized the nuclear translocation of phospho-Nrf2 and inhibited the altered level of autophagy factors. Taken together, our data indicated that Pirh2 is critically involved in STZ induced AD pathogenesis through its interaction with ER-chaperone GRP78, improves the neuronal connectivity, affects the altered level of chaperones, co-chaperones, & autophagic markers, and collectively inhibits the Aβ aggregation.

Keywords:  Alzheimer's disease; ER stress; Pirh2; amyloid aggregation; chaperone-mediated autophagy; ubiquitin proteasome system

DOI:  https://doi.org/10.1002/jcp.31134
Res Sq. 2023 Oct 13. pii: rs.3.rs-3439102. [Epub ahead of print]

Anionic Nanoplastic Contaminants Promote Parkinson's Disease-Associated α-Synuclein Aggregation.

Zhiyong Liu, Arpine Sokratian, Addison Duda, Enquan Xu, Christina Stanhope, Amber Fu, Samuel Strader, Huizhong Li, Yuan Yuan, Benjamin Bobay, Joana Sipe, Ketty Bai, Iben Lundgaard, Na Liu, Belinda Hernandez, Catherine Bowes Rickman, Sara Miller, Andrew West.

Recent studies have identified increasing levels of nanoplastic pollution in the environment. Here we find that anionic nanoplastic contaminants potently precipitate the formation and propagation of α-synuclein protein fibrils through a high-affinity interaction with the amphipathic and non-amyloid component (NAC) domains in α-synuclein. Nanoplastics can internalize in neurons through clathrin-dependent endocytosis, causing a mild lysosomal impairment that slows the degradation of aggregated α-synuclein. In mice, nanoplastics combine with α-synuclein fibrils to exacerbate the spread of α-synuclein pathology across interconnected vulnerable brain regions, including the strong induction of α-synuclein inclusions in dopaminergic neurons in the substantia nigra. These results highlight a potential link for further exploration between nanoplastic pollution and α-synuclein aggregation associated with Parkinson's disease and related dementias.

DOI: https://doi.org/10.21203/rs.3.rs-3439102/v1
Life (Basel). 2023 Sep 23. pii: 1954. [Epub ahead of print]13(10):

Interaction of Proteins Involved in Neuronal Proteinopathies.

Konstantin Y Kulichikhin, Oksana A Malikova, Anastasia E Zobnina, Natalia M Zalutskaya, Aleksandr A Rubel.

  Proteinopathy is characterized by the accumulation of aggregates of a specific protein in a target organ, tissue, or cell. The aggregation of the same protein can cause different pathologies as single protein can adopt various amyloidogenic, disease-specific conformations. The conformation governs the interaction of amyloid aggregates with other proteins that are prone to misfolding and, thus, determines disease-specific spectrum of concomitant pathologies. In this regard, a detailed description of amyloid protein conformation as well as spectrum of its interaction with other proteins become a key point for drafting of precise description of the disease. The majority of clinical cases of neuronal proteinopathies is caused by the aggregation of rather limited range of amyloidogenic proteins. Here, we provided the characterization of pathologies, related to the aggregation of amyloid β peptide, tau protein, α-synuclein, TDP-43, and amylin, giving a short description of pathologies themselves, recent advances in elucidation of misfolded protein conformation, with emphasis on those protein aggregates extracted from biological samples, what is known about the interaction of this proteins, and the influence of this interaction on the progression of underlying disease and comorbidities.

Keywords:  TDP-43; amylin; amyloid β peptide; disease-specific conformation; protein interaction; protein misfolding; proteinopathy; tau protein; α-synuclein

DOI:  https://doi.org/10.3390/life13101954
J Biol Chem. 2023 Oct 25. pii: S0021-9258(23)02411-0. [Epub ahead of print] 105383

The Toxicities of A30P and A53T α-Synuclein Fibrils Can be Uniquely Altered by The Length and Saturation of Fatty Acids in Phosphatidylserine.

Abid Ali, Kiryl Zhaliazka, Tianyi Dou, Aidan P Holman, Dmitry Kurouski.

  Progressive degeneration of dopaminergic neurons in the midbrain, hypothalamus, and thalamus is a hallmark of Parkinson's disease. Neuronal death is linked to the abrupt aggregation of α-synuclein (α-syn), a small protein that regulates vesicle trafficking in synaptic clefts. Studies of families with a history of PD revealed several mutations in α-syn including A30P and A53T that are linked to the early onset of this pathology. Numerous pieces of evidence indicate that lipids can alter the rate of protein aggregation, as well as modify the secondary structure and toxicity of amyloid oligomers and fibrils. However, the role of lipids in the stability of α-syn mutants remains unclear. In this study, we investigate the effect of phosphatidylserine (PS), an anionic lipid that plays an important role in the recognition of apoptotic cells by macrophages, in the stability of WT, A30P, and A53T α-syn. We found PS with different lengths and saturation of fatty acids (FAs) accelerated the rate of WT and A30P aggregation. At the same time, the opposite effect was observed for most PS on A53T. We also found that PS with different lengths and saturation of FAs change the secondary structure and toxicities of WT, A30P, and A53T fibrils. These results indicate that lipids can play an important role in the onset and spread of familial PD.

Keywords:  AFM-IR; fibrils; oligomers; phosphatidylserine; toxicity; α-Synuclein

DOI:  https://doi.org/10.1016/j.jbc.2023.105383
J Prev Alzheimers Dis. 2023 ;10(4): 661-668

Opportunities for Cellular Rejuvenation in Alzheimer's Disease: How Epigenetic Reprogramming and Chaperone-Mediated Autophagy Are Enabling Next Generation Therapeutic Approaches.

S Rosenzweig-Lipson.

  Age remains the largest risk factor in the development of neurodegenerative diseases such as Alzheimer's disease (AD). Numerous cellular hallmarks of aging contribute to the advancement of the pathologies associated with neurodegenerative disease. Not all cellular hallmarks of aging are independent and several fall into the broader category of cellular rejuvenation, which captures returning cells to a more youthful, improved functional state. Cellular rejuvenation is quickly becoming a hot topic in the development of novel therapeutic modalities for a range of diseases. Therapeutic approaches utilizing cellular rejuvenation technologies are rapidly advancing and will represent the next phase of AD therapeutics. This review focuses on two important processes, epigenetic reprogramming, and chaperone-mediated autophagy (CMA) that play a critical role in aging and in neurodegenerative diseases and the potential therapeutic approaches (gene therapy, small molecule) towards targeting these mechanisms. In aging and in AD, epigenetic changes on DNA (e.g., hypermethylation on CpG islands) lead to alterations in gene expression. Partial epigenetic reprogramming utilizes transcription factors to remove the epigenetic marks and to rejuvenate cells to a more youthful state. During aging and in neurodegenerative disorders, CMA becomes impaired resulting in a buildup of proteins known to be associated with neurodegenerative pathologies. The protein buildups lead to aggregates that preclude proteostasis leading to cell toxicity. Small-molecule CMA activators restore proteostasis and limit toxicity enabling cellular rejuvenation.

Keywords:  Epigenetic reprogramming; LAMP2A; OSK; cellular rejuvenation; chaperone-mediated autophagy

DOI:  https://doi.org/10.14283/jpad.2023.106
Curr Mol Med. 2023 Oct 24.

Targeting GM2 Ganglioside Accumulation in Dementia: Current Therapeutic Approaches and Future Directions.

Sanjesh Kumar, Siva Prasad Panda.

  Dementia in neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB) is a progressive neurological condition affecting millions worldwide. The amphiphilic molecule GM2 gangliosides are abundant in the human brain and play important roles in neuronal development, intercellular recognition, myelin stabilization, and signal transduction. GM2 ganglioside's degradation requires hexosaminidase A (HexA), a heterodimer composed of an α subunit encoded by HEXA and a β subunit encoded by HEXB. The hydrolysis of GM2 also requires a non-enzymatic protein, the GM2 activator protein (GM2-AP), encoded by GM2A. Pathogenic mutations of HEXA, HEXB, and GM2A are responsible for autosomal recessive diseases known as GM2 gangliosidosis, caused by the excessive intralysosomal accumulation of GM2 gangliosides. In AD, PD and DLB, GM2 ganglioside accumulation is reported to facilitate Aβ and α-synuclein aggregation into toxic oligomers and plaques through activation of downstream signaling pathways, such as protein kinase C (PKC) and oxidative stress factors. This review explored the potential role of GM2 ganglioside alteration in toxic protein aggregations and its related signaling pathways leading to neurodegenerative diseases. Further review explored potential therapeutic approaches, which include synthetic and phytomolecules targeting GM2 ganglioside accumulation in the brain, holding a promise for providing new and effective management for dementia.

Keywords:  Dementia; GM2 ganglioside; GM2 gene; PKC; potential therapy; synaptic loss

DOI:  https://doi.org/10.2174/0115665240264547231017110613
Metabolites. 2023 Oct 20. pii: 1100. [Epub ahead of print]13(10):

Adenosine Triphosphate (ATP) and Protein Aggregation in Age-Related Vision-Threatening Ocular Diseases.

Jack V Greiner, Thomas Glonek.

  Protein aggregation is the etiopathogenesis of the three most profound vision-threatening eye diseases: age-related cataract, presbyopia, and age-related macular degeneration. This perspective organizes known information on ATP and protein aggregation with a fundamental unrecognized function of ATP. With recognition that maintenance of protein solubility is related to the high intracellular concentration of ATP in cells, tissues, and organs, we hypothesize that (1) ATP serves a critical molecular function for organismal homeostasis of proteins and (2) the hydrotropic feature of ATP prevents pathological protein aggregation while assisting in the maintenance of protein solubility and cellular, tissue, and organismal function. As such, the metabolite ATP plays an extraordinarily important role in the prevention of protein aggregation in the leading causes of vision loss or blindness worldwide.

Keywords:  age; eye; hydration; hydrotrope; ice-like; lens protein; organized water; retinal protein; water of hydration

DOI:  https://doi.org/10.3390/metabo13101100
Biomolecules. 2023 Oct 02. pii: 1476. [Epub ahead of print]13(10):

The Effects of Lipids on α-Synuclein Aggregation In Vitro.

Jennifer Ramirez, Samantha X Pancoe, Elizabeth Rhoades, E James Petersson.

  The small neuronal protein α-synuclein (αS) is found in pre-synaptic terminals and plays a role in vesicle recycling and neurotransmission. Fibrillar aggregates of αS are the hallmark of Parkinson's disease and related neurodegenerative disorders. In both health and disease, interactions with lipids influence αS's structure and function, prompting much study of the effects of lipids on αS aggregation. A comprehensive collection (126 examples) of aggregation rate data for various αS/lipid combinations was presented, including combinations of lipid variations and mutations or post-translational modifications of αS. These data were interpreted in terms of lipid structure to identify general trends. These tabulated data serve as a resource for the community to help in the interpretation of aggregation experiments with lipids and to be potentially used as inputs for computational models of lipid effects on aggregation.

Keywords:  aggregation; lipid; α-synuclein

DOI:  https://doi.org/10.3390/biom13101476
ACS Appl Bio Mater. 2023 Oct 27.

Nontoxic Aggregation-Induced Emissive Luminogen for the Detection of Amyloid Fibrils and Cellular Protein Aggregates.

Saurajit Ghosh, Lavanya Suresh Iyer, Rajdeep Chowdhury, Partha Sarathi Addy.

  Protein misfolding and aggregation resulting in amyloid formation is directly linked to various diseases. Hence, there is keen interest in developing probes for the selective detection of such misfolded aggregated proteins. In this paper, we have shown the use of a nontoxic aggregation-induced emissive luminogen (AIEgen), BIDCPV, for the selective detection of insulin amyloid fibrils and their various stages of formation. We further verified the selective response of BIDCPV toward amyloid fibrils by testing the probe against Aβ 42 peptides, which is well known to form the fibrils. Additionally, the low toxicity, efficient cellular internalization capability, and photostability make BIDCPV a unique candidate for sensing protein aggregates inside mammalian cells.

Keywords:  Aggregation-induced emission; Amyloid fibrils; Confocal microscopy; Fluorescence; Insulin

DOI:  https://doi.org/10.1021/acsabm.3c00704
Pharmaceuticals (Basel). 2023 Oct 20. pii: 1498. [Epub ahead of print]16(10):

Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend C. elegans Life- and Healthspan.

Samuel Kakraba, Srinivas Ayyadevara, Nirjal Mainali, Meenakshisundaram Balasubramaniam, Suresh Bowroju, Narsimha Reddy Penthala, Ramani Atluri, Steven W Barger, Sue T Griffin, Peter A Crooks, Robert J Shmookler Reis.

  Chronic, low-grade inflammation has been implicated in aging and age-dependent conditions, including Alzheimer's disease, cardiomyopathy, and cancer. One of the age-associated processes underlying chronic inflammation is protein aggregation, which is implicated in neuroinflammation and a broad spectrum of neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's diseases. We screened a panel of bioactive thiadiazolidinones (TDZDs) from our in-house library for rescue of protein aggregation in human-cell and C. elegans models of neurodegeneration. Among the tested TDZD analogs, PNR886 and PNR962 were most effective, significantly reducing both the number and intensity of Alzheimer-like tau and amyloid aggregates in human cell-culture models of pathogenic aggregation. A C. elegans strain expressing human Aβ1-42 in muscle, leading to AD-like amyloidopathy, developed fewer and smaller aggregates after PNR886 or PNR962 treatment. Moreover, age-progressive paralysis was reduced 90% by PNR886 and 75% by PNR962, and "healthspan" (the median duration of spontaneous motility) was extended 29% and 62%, respectively. These TDZD analogs also extended wild-type C. elegans lifespan by 15-30% (p < 0.001), placing them among the most effective life-extension drugs. Because the lead drug in this family, TDZD-8, inhibits GSK3β, we used molecular-dynamic tools to assess whether these analogs may also target GSK3β. In silico modeling predicted that PNR886 or PNR962 would bind to the same allosteric pocket of inactive GSK3β as TDZD-8, employing the same pharmacophore but attaching with greater avidity. PNR886 and PNR962 are thus compelling candidate drugs for treatment of tau- and amyloid-associated neurodegenerative diseases such as AD, potentially also reducing all-cause mortality.

Keywords:  Alzheimer’s disease; aggregation; glycogen synthase kinase 3β (GSK3β); molecular modeling; neurodegeneration; neurodegenerative disease; protein aggregation; proteostasis; thiadiazolidinones (TDZDs)

DOI:  https://doi.org/10.3390/ph16101498
Sci Rep. 2023 Oct 21. 13(1): 18024

Tau accumulation in degradative organelles is associated to lysosomal stress.

Ester Piovesana, Claudia Magrin, Matteo Ciccaldo, Martina Sola, Manolo Bellotto, Maurizio Molinari, Stéphanie Papin, Paolo Paganetti.

Neurodegenerative disorders are characterized by the brain deposition of insoluble amyloidogenic proteins, such as α-synuclein or Tau, and the concomitant deterioration of cell functions such as the autophagy-lysosomal pathway (ALP). The ALP is involved in the degradation of intracellular macromolecules including protein aggregates. ALP dysfunction due to inherited defects in lysosomal or non-lysosomal proteins causes a group of diseases called lysosomal storage disorders (LSD) because of abnormal accumulation of lysosomal degradation substrates. Supporting the contribution of ALP defects in neurodegenerative diseases, deposition of amyloidogenic proteins occurs in LSD. Moreover, heterozygous mutations of several ALP genes represent risk factors for Parkinson's disease. The reciprocal contribution of α-synuclein accumulation and lysosomal dysfunction have been extensively studied. However, whether this adverse crosstalk also embraces Tau pathology needs more investigation. Here, we show in human primary fibroblasts that Tau seeds isolated from the brain of Alzheimer's disease induce Tau accumulation in acidic degradative organelles and lysosomal stress. Furthermore, inhibition of glucocerebrosidase, a lysosomal enzyme mutated in Gaucher's disease and a main risk for Parkinson's disease, causes lysosomal dysfunction in primary fibroblasts and contributes to the accumulation of Tau. Considering the presence of Tau lesions in Parkinson's disease as well as in multiple neurodegenerative disorders including Alzheimer's disease, our data call for further studies on strategies to alleviate ALP dysfunction as new therapeutic opportunity for neurodegenerative diseases and LSD.

DOI: https://doi.org/10.1038/s41598-023-44979-7
Sci Adv. 2023 Oct 27. 9(43): eadh3457

Saturation mutagenesis of α-synuclein reveals monomer fold that modulates aggregation.

Julita Chlebowicz, William Russ, Dailu Chen, Anthony Vega, Steven Vernino, Charles L White, Josep Rizo, Lukasz A Joachimiak, Marc I Diamond.

α-Synuclein (aSyn) aggregation underlies neurodegenerative synucleinopathies. aSyn seeds are proposed to replicate and propagate neuronal pathology like prions. Seeding of aSyn can be recapitulated in cellular systems of aSyn aggregation; however, the mechanism of aSyn seeding and its regulation are not well understood. We developed an mEos-based aSyn seeding assay and performed saturation mutagenesis to identify with single-residue resolution positive and negative regulators of aSyn aggregation. We not only found the core regions that govern aSyn aggregation but also identified mutants outside of the core that enhance aggregation. We identified local structure within the N terminus of aSyn that hinders the fibrillization propensity of its aggregation-prone core. Based on the screen, we designed a minimal aSyn fragment that shows a ~4-fold enhancement in seeding activity and enabled discrimination of synucleinopathies. Our study expands the basic knowledge of aSyn aggregation and advances the design of cellular systems of aSyn aggregation to diagnose synucleinopathies based on protein conformation.

DOI: https://doi.org/10.1126/sciadv.adh3457
bioRxiv. 2023 Oct 03. pii: 2023.10.03.560761. [Epub ahead of print]

Localized synthesis of molecular chaperones sustains neuronal proteostasis.

Celia Alecki, Javeria Rizwan, Phuong Le, Suleima Jacob-Tomas, Stella Xu, Sandra Minotti, Tad Wu, Heather Durham, Gene W Yeo, Maria Vera.

Neurons are challenged to maintain proteostasis in neuronal projections, particularly with the physiological stress at synapses to support intercellular communication underlying important functions such as memory and movement control. Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. Using high-resolution fluorescent microscopy, we discovered that neurons localize a subset of chaperone mRNAs to their dendrites, particularly more proximal regions, and increase this asymmetric localization following proteotoxic stress through microtubule-based transport from the soma. The most abundant chaperone mRNA in dendrites encodes the constitutive heat shock protein 70, HSPA8. Proteotoxic stress in cultured neurons, induced by inhibiting proteasome activity or inducing oxidative stress, enhanced transport of Hspa8 mRNAs to dendrites and the percentage of mRNAs engaged in translation on mono and polyribosomes. Knocking down the ALS-related protein Fused in Sarcoma (FUS) and a dominant mutation in the heterogenous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) impaired stress-mediated localization of Hspa8 mRNA to dendrites in cultured murine motor neurons and human iPSC-derived neurons, respectively, revealing the importance of these RNA-binding proteins in maintaining proteostasis. These results reveal the increased dendritic localization and translation of the constitutive HSP70 Hspa8 mRNA as a crucial neuronal stress response to uphold proteostasis and prevent neurodegeneration.
SUMMARY: Localizing chaperones' mRNAs in neuronal dendrites is a novel on-demand system to uphold proteostasis upon stress.

DOI: https://doi.org/10.1101/2023.10.03.560761
Chem Biol Interact. 2023 Oct 24. pii: S0009-2797(23)00450-7. [Epub ahead of print] 110783

Butyrylcholinesterase signal sequence self-aggregates and enhances amyloid fibril formation in vitro.

Jacek Jasiecki, Monika Targońska, Anna Janaszak-Jasiecka, Leszek Kalinowski, Krzysztof Waleron, Bartosz Wasąg.

  Alzheimer's disease (AD) pathogenesis has been attributed to extracellular aggregates of amyloid β (Aβ) plaques and neurofibrillary tangles in the human brain. It has been reported that butyrylcholinesterase (BChE) also accumulates in the brain Aβ plaques in AD. We have previously found that the BChE substitution in 5'UTR caused an in-frame N-terminal extension of 41 amino acids of the BChE signal peptide. The resultant variant with a 69 amino acid signal peptide, designated N-BChE, could play a role in AD development. Here, we report that the signal sequence of the BChE, if produced in an extended 69 aa version, can self-aggregate and could form seeds that enhance amyloid fibril formation in vitro in a dose-dependent manner and create larger co-aggregates. Similar phenomena could have been observed in the human brain if such an extended form of the signal sequence had been, in some circumstances, translated.

Keywords:  Aggregation; Alzheimer's disease; Amyloid; Butyrylcholinesterase; Cross-seeding; Pseudocholinesterase

DOI:  https://doi.org/10.1016/j.cbi.2023.110783
ACS Chem Neurosci. 2023 Oct 27.

Understanding the Molecular Mechanisms of Polyphenol Inhibition of Amyloid β Aggregation.

Yin-Lei Han, Huan-Huan Yin, Chao Xiao, Matthew T Bernards, Yi He, Yi-Xin Guan.

  Alzheimer's disease (AD) is highly associated with self-aggregation of amyloid β (Aβ) proteins into fibrils. Inhibition of Aβ aggregation by polyphenols is one of the major therapeutic strategies for AD. Among them, four polyphenols (brazilin, resveratrol, hematoxylin, and rosmarinic acid) have been reported to be effective at inhibiting Aβ aggregation, but the inhibition mechanisms are still unclear. In this work, these four polyphenols were selected to explore their interactions with the Aβ17-42 pentamer by molecular dynamics simulation. All four polyphenols can bind to the pentamer tightly but prefer different binding sites. Conversion of the β-sheet to the random coil, fewer interchain hydrogen bonds, and weaker salt bridges were observed after binding. Interestingly, different Aβ17-42 pentamer destabilizing mechanisms for resveratrol and hematoxylin were found. Resveratrol inserts into the hydrophobic core of the pentamer by forming hydrogen bonds with Asp23 and Lys28, while hematoxylin prefers to bind beside chain A of the pentamer, which leads to β-sheet offset and dissociation of the β1 sheet of chain E. This work reveals the interactions between the Aβ17-42 pentamer and four polyphenols and discusses the relationship between inhibitor structures and their inhibition mechanisms, which also provides useful guidance for screening effective Aβ aggregation inhibitors and drug design against AD.

Keywords:  amyloid β aggregation; hematoxylin; inhibition mechanisms; molecular dynamics simulation; polyphenol; resveratrol

DOI:  https://doi.org/10.1021/acschemneuro.3c00586
Aging Cell. 2023 Oct 27. e14013

A short peptide protects from age-onset proteotoxicity.

Hassan Elsana, Reut Bruck-Haimson, Huadong Zhu, Atif Ahmed Siddiqui, Adam Zaretsky, Irit Cohen, Hana Boocholez, Noa Roitenberg, Lorna Moll, Inbar Plaschkes, David Naor, Ehud Cohen.

  Aberrant protein aggregation jeopardizes cellular functionality and underlies the development of a myriad of late-onset maladies including Alzheimer's disease (AD) and Huntington's disease (HD). Accordingly, molecules that mitigate the toxicity of hazardous protein aggregates are of great interest as potential future therapeutics. Here we asked whether a small peptide, composed of five amino acids (5MER peptide) that was derived from the human pro-inflammatory CD44 protein, could protect model nematodes from the toxicity of aggregative proteins that underlie the development of neurodegenerative disorders in humans. We found that the 5MER peptide mitigates the toxicity that stems from both; the AD-causing Aβ peptide and a stretch of poly-glutamine that is accountable for the development of several disorders including HD, while minimally affecting lifespan. This protection was dependent on the activity of aging-regulating transcription factors and associated with enhanced Aβ and polyQ35-YFP aggregation. A transcriptomic analysis unveiled that the peptide modifies signaling pathways, thereby modulating the expression of various genes, including these, which are known as protein homeostasis (proteostasis) regulators such as txt-13 and modifiers of proteasome activity. The knockdown of txt-13 protects worms from proteotoxicity to the same extent as the 5MER peptide, suggesting that the peptide activates the transcellular chaperone signaling to promote proteostasis. Together, our results propose that the 5MER peptide should be considered as a component of future therapeutic cocktails for the treatment of neurodegenerative maladies.

Keywords:  C. elegans; aging; neurodegeneration; proteostasis; trans chaperone signaling

DOI:  https://doi.org/10.1111/acel.14013
Res Sq. 2023 Oct 19. pii: rs.3.rs-3417076. [Epub ahead of print]

Retromer stabilization using a pharmacological chaperone protects in an α-synuclein based mouse model of Parkinson's.

Simona Eleuteri, Tracy Shi Zhang Fang, Gianni Cutillo, Michele Persico, David K Simon.

Background In the present study we assessed the protective effects of a pharmacological approach to stabilize the retromer complex in a PD mouse model. Missense mutations in the VPS35 gene are a rare cause of familial PD. The VPS35 protein is a subunit of the retromer cargo recognition complex and has a variety of functions within neurons, many of which are potentially relevant for the pathophysiology of PD. Prior studies have revealed a role for the retromer complex in controlling accumulation and clearance of α-synuclein aggregates. We previously identified an aminoguanidine hydrazone, 1,3 phenyl bis guanylhydrazone (compound 2a), as a pharmacological stabilizer of the retromer complex that increases retromer subunit protein levels and function. Methods Here, we validate the efficacy of 2a in protecting against αSynuclein pathology and dopaminergic neuronal degeneration in a PD mouse model generated by unilateral injection of AAV-A53T-αSynuclein in the substantia nigra. Results Daily intraperitoneal administration of 2a at 10 mg/Kg for 100 days led to robust protection against behavioral deficits, dopaminergic neuronal loss and loss of striatal dopaminergic fibers and striatal monoamines. Treatment with 2a activated αSynuclein degradation pathways in the SN and led to significant reductions in aggregates and pathological αSynuclein. Conclusion These data suggest retromer stabilization as a promising therapeutic strategy for Parkinson's disease leading to neuroprotection of dopaminergic neurons and rescue in the accumulation of pathological and aggregates αSynuclein. We identified 2a compound as potential clinical drug candidate for future testing in Parkinson's disease patients.

DOI: https://doi.org/10.21203/rs.3.rs-3417076/v1
J Neurosci. 2023 Oct 26. pii: JN-RM-1318-23. [Epub ahead of print]

Nascent Aβ42 fibrillization in synaptic endosomes precedes plaque formation in a mouse model of Alzheimer's like β-amyloidosis.

Elizabeth A Eckman, Dana M Clausen, Santiago Solé-Domėnech, Chris W Lee, Cristina Sinobas-Pereira, Ryan J Domalewski, Michael R Nichols, Javier Pacheco-Quinto.

Accumulation of amyloid-β peptide (Aβ) aggregates in synapses may contribute to the profound synaptic loss characteristic of Alzheimer's disease (AD). The origin of synaptic Aβ aggregates remains elusive, but loss of endosomal proteostasis may trigger their formation.In this study we identified the synaptic compartments where Aβ accumulates and performed a longitudinal analysis of synaptosomes isolated from brains of TgCRND8 APP transgenic mice of either sex. To evaluate the specific contribution of Aβ-degrading protease endothelin-converting enzyme (ECE-1) to synaptic/endosomal Aβ homeostasis, we analyzed the effect of partial Ece1 knockout in brain and complete ECE1 knockout in SH-SY5Y cells. Global inhibition of ECE family members was used to further assess their role in preventing synaptic Aβ accumulation.Results showed that, before extracellular amyloid deposition, synapses were burdened with detergent-soluble Aβ monomers, oligomers, and fibrils. Levels of all soluble Aβ species declined thereafter, as Aβ42 turned progressively insoluble and accumulated in Aβ-producing synaptic endosomal vesicles with characteristics of multivesicular bodies. Accordingly, fibrillar Aβ was detected in brain exosomes. ECE-1 deficient mice had significantly increased endogenous synaptosomal Aβ42 levels and protease inhibitor experiments showed that in TgCRND8 mice, synaptic Aβ42 became nearly resistant to degradation by ECE-related proteases.Our study supports that Aβ accumulating in synapses is produced locally, within endosomes, and does not require the presence of amyloid plaques. ECE-1 is a determinant factor controlling the accumulation and fibrillization of nascent Aβ in endosomes and, in TgCRND8 mice, Aβ overproduction causes rapid loss of Aβ42 solubility that curtails ECE-mediated degradation.Significance StatementDeposition of aggregated Aβ in extracellular plaques is a defining feature of AD. Aβ aggregates also accumulate in synapses and may contribute to the profound synaptic loss and cognitive dysfunction typical of the disease. However, it is not clear whether synaptotoxic Aβ is mainly derived from plaques or if it is produced and aggregated locally, within affected synaptic compartments. Filling this knowledge gap is important for the development of an effective treatment for AD, as extracellular and intrasynaptic pools of Aβ may not be equally modulated by immunotherapies or other therapeutic approaches. In this manuscript we provide evidence that Aβ aggregates building up in synapses are formed locally, within synaptic endosomes, due to disruptions in nascent Aβ proteostasis.

DOI: https://doi.org/10.1523/JNEUROSCI.1318-23.2023
bioRxiv. 2023 Oct 02. pii: 2023.10.02.560545. [Epub ahead of print]

A New Role for RNA G-quadruplexes in Aging and Alzheimer's Disease.

Lena Kallweit, Eric D Hamlett, Hannah Saternos, Anah Gilmore, Ann-Charlotte Granholm, Scott Horowitz.

As the world population ages, new molecular targets in aging and Alzheimer's Disease (AD) are needed to combat the expected influx of new AD cases. Until now, the role of RNA structure in aging and neurodegeneration has largely remained unexplored. In this study, we examined human hippocampal postmortem tissue for the formation of RNA G-quadruplexes (rG4s) in aging and AD. We found that rG4 immunostaining strongly increased in prevalence in the hippocampus with both age and with AD severity. We further found that neurofibrillary tangles (NFTs) contained rG4s, that rG4 structure can drive tau aggregation, and that rG4 formation depended on APOE genotype in the human tissue examined. Combined with previous studies showing the dependence of rG4 structure on stress and the extreme power of rG4s at oligomerizing proteins, we propose a model of neurodegeneration in which chronic rG4 formation drives proteostasis collapse. We propose that further investigation of RNA structure in neurodegeneration is a critical avenue for future treatments and diagnoses.

DOI: https://doi.org/10.1101/2023.10.02.560545