bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2024‒04‒28
sixteen papers selected by
Verena Kohler, Umeå University
  1. Interplay of α-synuclein with Lipid Membranes: Cooperative Adsorption, Membrane Remodeling and Coaggregation.
  2. Alpha-Synuclein Aggregation Mechanism in the Presence of Nanomaterials.
  3. Proteostatic Remodeling of Small Heat Shock Chaperones─Crystallins by Ran-Binding Protein 2─and the Peptidyl-Prolyl cis-trans Isomerase and Chaperone Activities of Its Cyclophilin Domain.
  4. Polycatechols inhibit ferroptosis and modulate tau liquid-liquid phase separation to mitigate Alzheimer's disease.
  5. Characterizing Prion-Like Protein Aggregation: Emerging Nanopore-Based Approaches.
  6. Hyperacetylation mimetics within the tau filament core inhibits prion-like propagation of misfolded tau.
  7. Role of TFEB in Huntington's Disease.
  8. Hotspot site microenvironment in the deubiquitinase OTUB1 drives its stability and aggregation.
  9. Raman spectroscopy in the study of amyloid formation and phase separation.
  10. Geniposide and Harpagoside Functionalized Cerium Oxide Nanoparticles as a Potential Neuroprotective.
  11. Alpha-synuclein aggregates are phosphatase resistant.
  12. Involvement of the glymphatic/meningeal lymphatic system in Alzheimer's disease: insights into proteostasis and future directions.
  13. Research progress of PROTACs for neurodegenerative diseases therapy.
  14. Copper enhances aggregational toxicity of mutant huntingtin in a Drosophila model of Huntington's Disease.
  15. Biophysical Evidence for the Amyloid Formation of a Recombinant Rab2 Isoform of Leishmania donovani.
  16. Role of the Gut Microbiome and Bacterial Amyloids in the Development of Synucleinopathies.
  1. JACS Au. 2024 Apr 22. 4(4): 1250-1262
    Interplay of α-synuclein with Lipid Membranes: Cooperative Adsorption, Membrane Remodeling and Coaggregation.
    Katarzyna Makasewicz, Sara Linse, Emma Sparr.
      α-Synuclein is a small neuronal protein enriched at presynaptic termini. It is hypothesized to play a role in neurotransmitter release and synaptic vesicle cycling, while the formation of α-synuclein amyloid fibrils is associated with several neurodegenerative diseases, most notably Parkinson's Disease. The molecular mechanisms of both the physiological and pathological functions of α-synuclein remain to be fully understood, but in both cases, interactions with membranes play an important role. In this Perspective, we discuss several aspects of α-synuclein interactions with lipid membranes including cooperative adsorption, membrane remodeling and α-synuclein amyloid fibril formation in the presence of lipid membranes. We highlight the coupling between the different phenomena and their interplay in the context of physiological and pathological functions of α-synuclein.
    DOI:  https://doi.org/10.1021/jacsau.3c00579
  2. Biochemistry. 2024 Apr 26.
    Alpha-Synuclein Aggregation Mechanism in the Presence of Nanomaterials.
    Shahid A Malik, Somnath Mondal, Hanudatta S Atreya.
      Parkinson's disease (PD) is characterized by the toxic oligomeric and fibrillar phases formed by monomeric alpha-synuclein (α-syn). Certain nanoparticles have been demonstrated to promote protein aggregation, while other nanomaterials have been found to prevent the process. In the current work, we use nuclear magnetic resonance spectroscopy in conjunction with isothermal titration calorimetry to investigate the cause and mechanism of these opposing effects at the amino acid protein level. The interaction of α-syn with two types of nanomaterials was considered: citrate-capped gold nanoparticles (AuNPs) and graphene oxide (GO). In the presence of AuNPs, α-syn aggregation is accelerated, whereas in the presence of GO, aggregation is prevented. The study indicates that GO sequesters the NAC region of α-syn monomers through electrostatic and hydrophobic interactions, leading to a reduced elongation rate, and AuNPs leave the NAC region exposed while binding the N-terminus, leading to higher aggregation. The protein's inclination toward quicker aggregation is explained by the binding of the N-terminus of α-syn with the gold nanoparticles. Conversely, a comparatively stronger interaction with GO causes the nucleation and growth phases to be postponed and inhibits intermolecular interactions. Our finding offers novel experimental insights at the residue level regarding the aggregation of α-syn in the presence of various nanomaterials and creates new opportunities for the development of suitably functionalized nanomaterial-based therapeutic reagents against Parkinson's and other neurodegenerative diseases.
    DOI:  https://doi.org/10.1021/acs.biochem.3c00624
  3. ACS Chem Neurosci. 2024 Apr 24.
    Proteostatic Remodeling of Small Heat Shock Chaperones─Crystallins by Ran-Binding Protein 2─and the Peptidyl-Prolyl cis-trans Isomerase and Chaperone Activities of Its Cyclophilin Domain.
    Hemangi Patil, Haiqing Yi, Kyoung-In Cho, Paulo A Ferreira.
      Disturbances in protein phase transitions promote protein aggregation─a neurodegeneration hallmark. The modular Ran-binding protein 2 (Ranbp2) is a cytosolic molecular hub for rate-limiting steps of phase transitions of Ran-GTP-bound protein ensembles exiting nuclear pores. Chaperones also regulate phase transitions and proteostasis by suppressing protein aggregation. Ranbp2 haploinsufficiency promotes the age-dependent neuroprotection of the chorioretina against phototoxicity by proteostatic regulations of neuroprotective substrates of Ranbp2 and by suppressing the buildup of polyubiquitylated substrates. Losses of peptidyl-prolyl cis-trans isomerase (PPIase) and chaperone activities of the cyclophilin domain (CY) of Ranbp2 recapitulate molecular effects of Ranbp2 haploinsufficiency. These CY impairments also stimulate deubiquitylation activities and phase transitions of 19S cap subunits of the 26S proteasome that associates with Ranbp2. However, links between CY moonlighting activity, substrate ubiquitylation, and proteostasis remain incomplete. Here, we reveal the Ranbp2 regulation of small heat shock chaperones─crystallins in the chorioretina by proteomics of mice with total or selective modular deficits of Ranbp2. Specifically, loss of CY PPIase of Ranbp2 upregulates αA-Crystallin, which is repressed in adult nonlenticular tissues. Conversely, impairment of CY's chaperone activity opposite to the PPIase pocket downregulates a subset of αA-Crystallin's substrates, γ-crystallins. These CY-dependent effects cause age-dependent and chorioretinal-selective declines of ubiquitylated substrates without affecting the chorioretinal morphology. A model emerges whereby inhibition of Ranbp2's CY PPIase remodels crystallins' expressions, subdues molecular aging, and preordains the chorioretina to neuroprotection by augmenting the chaperone capacity and the degradation of polyubiquitylated substrates against proteostatic impairments. Further, the druggable Ranbp2 CY holds pan-therapeutic potential against proteotoxicity and neurodegeneration.
    Keywords:  Ran-binding protein 2 (Ranbp2); chaperone; crystallins; cyclophilin; heat shock proteins; peptidyl-prolyl cis−trans isomerase (PPIase); proteostasis; proteotoxicity
    DOI:  https://doi.org/10.1021/acschemneuro.3c00792
  4. Mater Horiz. 2024 Apr 22.
    Polycatechols inhibit ferroptosis and modulate tau liquid-liquid phase separation to mitigate Alzheimer's disease.
    Hariharan Moorthy, Madhu Ramesh, Dikshaa Padhi, Prayasee Baruah, Thimmaiah Govindaraju.
      Alzheimer's disease (AD) is a complex neurodegenerative disorder that affects learning, memory, and cognition. Current treatments targeting amyloid-β (Aβ) and tau have shown limited effectiveness, necessitating further research on the aggregation and toxicity mechanisms. One of these mechanisms involves the liquid-liquid phase separation (LLPS) of tau, contributing to the formation of pathogenic tau aggregates, although their conformational details remain elusive. Another mechanism is ferroptosis, a type of iron-dependent lipid peroxidation-mediated cell death, which has been implicated in AD. There is a lack of therapeutic strategies that simultaneously target amyloid toxicity and ferroptosis. This study aims to explore the potential of polycatechols, PDP and PLDP, consisting of dopamine and L-Dopa, respectively, as multifunctional agents to modulate the pathological nexus between ferroptosis and AD. Polycatechols were found to sequester the labile iron pool (LIP), inhibit Aβ and tau aggregation, scavenge free radicals, protect mitochondria, and prevent ferroptosis, thereby rescuing neuronal cell death. Interestingly, PLDP promotes tau LLPS, and modulates their intermolecular interactions to inhibit the formation of toxic tau aggregates, offering a conceptually innovative approach to tackle tauopathies. This is a first-of-its-kind polymer-based integrative approach that inhibits ferroptosis, counteracts amyloid toxicity, and modulates tau LLPS to mitigate the multifaceted toxicity of AD.
    DOI:  https://doi.org/10.1039/d4mh00023d
  5. Small Methods. 2024 Apr 21. e2400058
    Characterizing Prion-Like Protein Aggregation: Emerging Nanopore-Based Approaches.
    Nathan Meyer, Joan Torrent, Sébastien Balme.
      Prion-like protein aggregation is characteristic of numerous neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. This process involves the formation of aggregates ranging from small and potentially neurotoxic oligomers to highly structured self-propagating amyloid fibrils. Various approaches are used to study protein aggregation, but they do not always provide continuous information on the polymorphic, transient, and heterogeneous species formed. This review provides an updated state-of-the-art approach to the detection and characterization of a wide range of protein aggregates using nanopore technology. For each type of nanopore, biological, solid-state polymer, and nanopipette, discuss the main achievements for the detection of protein aggregates as well as the significant contributions to the understanding of protein aggregation and diagnostics.
    Keywords:  amyloid fibers; nanopore; prion‐like proteins oligomers; single‐molecule techniques
    DOI:  https://doi.org/10.1002/smtd.202400058
  6. bioRxiv. 2024 Apr 15. pii: 2024.04.12.589253. [Epub ahead of print]
    Hyperacetylation mimetics within the tau filament core inhibits prion-like propagation of misfolded tau.
    Ethan D Smith, Robert McKenna, Mario Mietzsch, David R Borchelt, Stefan Prokop, Paramita Chakrabarty.
      Acetylation of key Lysine residues characterizes aggregates of the microtubule-associated protein tau constituting the neuropathological hallmark of many neurodegenerative diseases, such as Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP). This has led to the idea that acetylation influences tau aggregation. Using a HEK293 cell-based aggregation assay, we tested whether acetylation-mimicking substitutions (K→Q) on five AD-associated acetyl-modified sites (AcK-311, 353, 369, 370, 375) influenced its propensity to aggregate when exposed to tau seeds derived from two clinically distinctive diseases - AD and PSP. In combination, the presence of 5K→Q sites ablated tau aggregation induced by seeds from both AD and PSP patients, indicating that acetylation within the filament core domain of tau could have an inhibitory effect on seed-mediated aggregation. We had previously identified that a phosphorylation-mimetic on Ser305 (S→E) abrogated tau aggregation by seeds from AD patients, without affecting seeding by PSP patients. Combining the S305→E to the 5K→Q acetyl-modified sites, we found that this tau could now be seeded only by PSP patients, but not by AD patients, confirming Ser305 as a critical determinant of strain-specific tau seeding. On the other hand, acetylation-nullifying substitutions (K→R or K→A) on these same Lys sites did not alter tau seeding abilities compared to the parental tau construct. Notably, the combined acetylation-nullifying Alanine substitutions on these 5 Lys sites resulted in spontaneous self-aggregation, with the filaments resembling amorphous deposits. All together, we demonstrate that cooperative acetyl-occupancy in the tau filament core influences seeded propagation of misfolded tau as well as drives self-aggregation.
    DOI:  https://doi.org/10.1101/2024.04.12.589253
  7. Biology (Basel). 2024 Apr 04. pii: 238. [Epub ahead of print]13(4):
    Role of TFEB in Huntington's Disease.
    Javier Ojalvo-Pacheco, Sokhna M S Yakhine-Diop, José M Fuentes, Marta Paredes-Barquero, Mireia Niso-Santano.
      Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expansion of the CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. This expansion leads to a polyglutamine (polyQ) tract at the N-terminal end of HTT, which reduces the solubility of the protein and promotes its accumulation. Inefficient clearance of mutant HTT (mHTT) by the proteasome or autophagy-lysosomal system leads to accumulation of oligomers and toxic protein aggregates in neurons, resulting in impaired proteolytic systems, transcriptional dysregulation, impaired axonal transport, mitochondrial dysfunction and cellular energy imbalance. Growing evidence suggests that the accumulation of mHTT aggregates and autophagic and/or lysosomal dysfunction are the major pathogenic mechanisms underlying HD. In this context, enhancing autophagy may be an effective therapeutic strategy to remove protein aggregates and improve cell function. Transcription factor EB (TFEB), a master transcriptional regulator of autophagy, controls the expression of genes critical for autophagosome formation, lysosomal biogenesis, lysosomal function and autophagic flux. Consequently, the induction of TFEB activity to promote intracellular clearance may be a therapeutic strategy for HD. However, while some studies have shown that overexpression of TFEB facilitates the clearance of mHTT aggregates and ameliorates the disease phenotype, others indicate such overexpression may lead to mHTT co-aggregation and worsen disease progression. Further studies are necessary to confirm whether TFEB modulation could be an effective therapeutic strategy against mHTT-mediated toxicity in different disease models.
    Keywords:  Huntington’s disease; TFEB; autophagy; lysosome; mHTT
    DOI:  https://doi.org/10.3390/biology13040238
  8. J Biol Chem. 2024 Apr 23. pii: S0021-9258(24)01816-7. [Epub ahead of print] 107315
    Hotspot site microenvironment in the deubiquitinase OTUB1 drives its stability and aggregation.
    Sushanta Majumder, Mitul Srivastava, Parvez Alam, Sandhini Saha, Raniki Kumari, Ajay Kumar Chand, Shailendra Asthana, Sobhan Sen, Tushar Kanti Maiti.
      Lewy bodies (LB) are aberrant protein accumulations observed in the brain cells of individuals affected by Parkinson's disease (PD). A comprehensive analysis of LB proteome identified over a hundred proteins, many co-enriched with α-synuclein, a major constituent of LB. Within this context, OTUB1, a deubiquitinase detected in LB, exhibits amyloidogenic properties, yet the mechanisms underlying its aggregation remain elusive. In this study, we identify two critical sites in OTUB1-namely, positions 133 and 173- that significantly impact its amyloid aggregation. Substituting alanine at position 133 and lysine at position 173 enhances both thermodynamic and kinetic stability, effectively preventing amyloid aggregation. Remarkably, lysine at position 173 demonstrates the highest stability without compromising enzymatic activity. The increased stability and inhibition of amyloid aggregation are attributed mainly to the changes in the specific microenvironment at the hotspot. In our exploration of the in-vivo co-occurrence of α-synuclein and OTUB1 in LB, we observed a synergistic modulation of each other's aggregation. Collectively, our study unveils the molecular determinants influencing OTUB1 aggregation, shedding light on the role of specific residues in modulating aggregation kinetics and structural transition. These findings contribute valuable insights into the complex interplay of amino acid properties and protein aggregation, with potential implications for understanding broader aspects of protein folding and aggregation phenomena.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107315
  9. Biochem Soc Trans. 2024 Apr 26. pii: BST20230599. [Epub ahead of print]
    Raman spectroscopy in the study of amyloid formation and phase separation.
    Sashary Ramos, Jennifer C Lee.
      Neurodegenerative diseases, such as Alzheimer's and Parkinson's, share a common pathological feature of amyloid structure accumulation. However, the structure-function relationship between these well-ordered, β-sheet-rich, filamentous protein deposits and disease etiology remains to be defined. Recently, an emerging hypothesis has linked phase separation, a process involved in the formation of protein condensates, to amyloid formation, suggesting that liquid protein droplets serve as loci for amyloid initiation. To elucidate how these processes contribute to disease progression, tools that can directly report on protein secondary structural changes are needed. Here, we review recent studies that have demonstrated Raman spectroscopy as a powerful vibrational technique for interrogating amyloid structures; one that offers sensitivity from the global secondary structural level to specific residues. This probe-free technique is further enhanced via coupling to a microscope, which affords structural data with spatial resolution, known as Raman spectral imaging (RSI). In vitro and in cellulo applications of RSI are discussed, highlighting studies of protein droplet aging, cellular internalization of fibrils, and Raman imaging of intracellular water. Collectively, utilization of the myriad Raman spectroscopic methods will contribute to a deeper understanding of protein conformational dynamics in the complex cellular milieu and offer potential clinical diagnostic capabilities for protein misfolding and aggregation processes in disease states.
    Keywords:  amyloid; imaging techniques; phase separation; protein aggregation; raman spectroscopy
    DOI:  https://doi.org/10.1042/BST20230599
  10. Int J Mol Sci. 2024 Apr 11. pii: 4262. [Epub ahead of print]25(8):
    Geniposide and Harpagoside Functionalized Cerium Oxide Nanoparticles as a Potential Neuroprotective.
    Rosa Martha Pérez Gutiérrez, Luis Miguel Rodríguez-Serrano, José Fidel Laguna-Chimal, Mónica de la Luz Corea, Silvia Patricia Paredes Carrera, Julio Téllez Gomez.
      Alzheimer's disease is associated with protein aggregation, oxidative stress, and the role of acetylcholinesterase in the pathology of the disease. Previous investigations have demonstrated that geniposide and harpagoside protect the brain neurons, and cerium nanoparticles (CeO2 NPs) have potent redox and antioxidant properties. Thus, the effect of nanoparticles of Ce NPs and geniposide and harpagoside (GH/CeO2 NPs) on ameliorating AD pathogenesis was established on AlCl3-induced AD in mice and an aggregation proteins test in vitro. Findings of spectroscopy analysis have revealed that GH/CeO2 NPs are highly stable, nano-size, spherical in shape, amorphous nature, and a total encapsulation of GH in cerium. Treatments with CeO2 NPs, GH/CeO2 NPs, and donepezil used as positive control inhibit fibril formation and protein aggregation, protect structural modifications in the BSA-ribose system, have the ability to counteract Tau protein aggregation and amyloid-β1-42 aggregation under fibrillation condition, and are able to inhibit AChE and BuChE. While the GH/CeO2 NPs, treatment in AD induced by AlCl3 inhibited amyloid-β1-42, substantially enhanced the memory, the cognition coordination of movement in part AD pathogenesis may be alleviated through reducing amyloidogenic pathway and AChE and BuChE activities. The findings of this work provide important comprehension of the chemoprotective activities of iridoids combined with nanoparticles. This could be useful in the development of new therapeutic methods for the treatment of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; acetylcholinesterase; amyloid-β1–42; butyrylcholinesterase; cognitive performance; nanoparticles; tau protein
    DOI:  https://doi.org/10.3390/ijms25084262
  11. bioRxiv. 2024 Apr 09. pii: 2023.11.20.567854. [Epub ahead of print]
    Alpha-synuclein aggregates are phosphatase resistant.
    S G Choi, T Tittle, D Garcia-Prada, J H Kordower, R Melki, B A Killinger.
      Alpha-synuclein (αsyn) is an intrinsically disordered protein that aggregates in the brain in several neurodegenerative diseases collectively called synucleinopathies. Phosphorylation of αsyn at serine 129 (PSER129) was considered rare in the healthy human brain but is enriched in pathological αsyn aggregates and is used as a specific marker for disease inclusions. However, recent observations challenge this assumption by demonstrating that PSER129 results from neuronal activity and can be readily detected in the non-diseased mammalian brain. Here, we investigated experimental conditions under which two distinct PSER129 pools, namely endogenous-PSER129 and aggregated-PSER129, could be detected and differentiated in the mammalian brain. Results showed that in the wild-type (WT) mouse brain, perfusion fixation conditions greatly influenced the detection of endogenous-PSER129, with endogenous-PSER129 being nearly undetectable after delayed perfusion fixation (30-minute and 1-hour postmortem interval). Exposure to anesthetics (e.g., Ketamine or xylazine) before perfusion did not significantly influence endogenous-PSER129 detection or levels. In situ, non-specific phosphatase calf alkaline phosphatase (CIAP) selectively dephosphorylated endogenous-PSER129 while αsyn preformed fibril (PFF)-seeded aggregates and genuine disease aggregates (Lewy pathology and Papp-Lantos bodies in Parkinson's disease and multiple systems atrophy brain, respectively) were resistant to CIAP-mediated dephosphorylation. The phosphatase resistance of aggregates was abolished by sample denaturation, and CIAP-resistant PSER129 was closely associated with proteinase K (PK)-resistant αsyn (i.e., a marker of aggregation). CIAP pretreatment allowed for highly specific detection of seeded αsyn aggregates in a mouse model that accumulates non-aggregated-PSER129. We conclude that αsyn aggregates are impervious to phosphatases, and CIAP pretreatment increases detection specificity for aggregated-PSER129, particularly in well-preserved biological samples (e.g., perfusion fixed or flash-frozen mammalian tissues) where there is a high probability of interference from endogenous-PSER129. Our findings have important implications for the mechanism of PSER129-accumulation in the synucleinopathy brain and provide a simple experimental method to differentiate endogenous-from aggregated PSER129.Significance Statement: Phosphorylated alpha-synuclein (PSER129) was widely regarded as a sensitive, specific marker for pathological aggregates in synucleinopathies until recent data demonstrated that PSER129 is abundant in the healthy mammalian nervous system and results from normal neuronal activity. Differentiating pathological (i.e., aggregated PSER129) and biological (non-aggregated PSER129) has thus become of critical importance to the field. Here, we describe our discovery that aggregated-PSER129 is impervious to enzymatic dephosphorylation. We leverage this discovery to develop a technique (CIAP-PSER129) to detect normal or pathological PSER129 selectively. Our technique allowed us to unambiguously differentiate pathological inclusions in brain regions and mouse models where excessive non-aggregated PSER129 severely limits the sensitivity of aggregate detection. CIAP-PSER129 is nondestructive and compatible with most downstream assays, including mass spectrometry-based peptide identification. These findings have important implications and utility for the synucleinopathy field and may have applicability to other neuropathological proteins (e.g., tau).
    DOI:  https://doi.org/10.1101/2023.11.20.567854
  12. Cell Mol Life Sci. 2024 Apr 23. 81(1): 192
    Involvement of the glymphatic/meningeal lymphatic system in Alzheimer's disease: insights into proteostasis and future directions.
    Kaoru Yamada, Takeshi Iwatsubo.
      BACKGROUND:  Alzheimer's disease (AD) is pathologically characterized by the abnormal accumulation of Aβ and tau proteins. There has long been a keen interest among researchers in understanding how Aβ and tau are ultimately cleared in the brain. The discovery of this glymphatic system introduced a novel perspective on protein clearance and it gained recognition as one of the major brain clearance pathways for clearing these pathogenic proteins in AD. This finding has sparked interest in exploring the potential contribution of the glymphatic/meningeal lymphatic system in AD. Furthermore, there is a growing emphasis and discussion regarding the possibility that activating the glymphatic/meningeal lymphatic system could serve as a novel therapeutic strategy against AD.OBJECTIVES:  Given this current research trend, the primary focus of this comprehensive review is to highlight the role of the glymphatic/meningeal lymphatic system in the pathogenesis of AD. The discussion will encompass future research directions and prospects for treatment in relation to the glymphatic/meningeal lymphatic system.
    Keywords:  Brain waster clearance; CNS lymphatics; CSF; ISF; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s00018-024-05225-z
  13. Bioorg Chem. 2024 Apr 18. pii: S0045-2068(24)00291-8. [Epub ahead of print]147 107386
    Research progress of PROTACs for neurodegenerative diseases therapy.
    Zhifang Cai, Zunhua Yang, Huilan Li, Yuanying Fang.
      Neurodegenerative diseases (NDD) are characterized by the gradual deterioration of neuronal function and integrity, resulting in an overall decline in brain function. The existing therapeutic options for NDD, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, fall short of meeting the clinical demand. A prominent pathological hallmark observed in numerous neurodegenerative disorders is the aggregation and misfolding of proteins both within and outside neurons. These abnormal proteins play a pivotal role in the pathogenesis of neurodegenerative diseases. Targeted degradation of irregular proteins offers a promising avenue for NDD treatment. Proteolysis-targeting chimeras (PROTACs) function via the ubiquitin-proteasome system and have emerged as a novel and efficacious approach in drug discovery. PROTACs can catalytically degrade "undruggable" proteins even at exceptionally low concentrations, allowing for precise quantitative control of aberrant protein levels. In this review, we present a compilation of reported PROTAC structures and their corresponding biological activities aimed at addressing NDD. Spanning from 2016 to present, this review provides an up-to-date overview of PROTAC-based therapeutic interventions. Currently, most protein degraders intended for NDD treatment remain in the preclinical research phase. Overcoming several challenges is imperative, including enhancing oral bioavailability and permeability across the blood-brain barrier, before these compounds can progress to clinical research or eventually reach the market. However, armed with an enhanced comprehension of the underlying pathological mechanisms and the emergence of innovative scaffolds for protein degraders, along with further structural optimization, we are confident that PROTAC possesses the potential to make substantial breakthroughs in the field of neurodegenerative diseases.
    Keywords:  Neurodegenerative disease; Protein degradation; Proteolytic targeting chimeras
    DOI:  https://doi.org/10.1016/j.bioorg.2024.107386
  14. Biochim Biophys Acta Mol Basis Dis. 2024 Jan;pii: S0925-4439(23)00294-6. [Epub ahead of print]1870(1): 166928
    Copper enhances aggregational toxicity of mutant huntingtin in a Drosophila model of Huntington's Disease.
    Amanda G Lobato, Natalie Ortiz-Vega, Yi Zhu, Deepa Neupane, Katlyn K Meier, R Grace Zhai.
      Huntington's disease (HD) is a progressive neurodegenerative disorder with clinical presentations of moderate to severe cognitive, motor, and psychiatric disturbances. HD is caused by the trinucleotide repeat expansion of CAG of the huntingtin (HTT) gene. The mutant HTT protein containing pathological polyglutamine (polyQ) extension is prone to misfolding and aggregation in the brain. It has previously been observed that copper and iron concentrations are increased in the striata of post-mortem human HD brains. Although it has been shown that the accumulation of mutant HTT protein can interact with copper, the underlying HD progressive phenotypes due to copper overload remains elusive. Here, in a Drosophila model of HD, we showed that copper induces dose-dependent aggregational toxicity and enhancement of Htt-induced neurodegeneration. Specifically, we found that copper increases mutant Htt aggregation, enhances the accumulation of Thioflavin S positive β-amyloid structures within Htt aggregates, and consequently alters autophagy in the brain. Administration of copper chelator D-penicillamine (DPA) through feeding significantly decreases β-amyloid aggregates in the HD pathological model. These findings reveal a direct role of copper in potentiating mutant Htt protein-induced aggregational toxicity, and further indicate the potential impact of environmental copper exposure in the disease onset and progression of HD.
    Keywords:  Aggregates; Chelation; Copper; Huntingtin; Huntington's disease
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166928
  15. Protein Pept Lett. 2024 Apr 24.
    Biophysical Evidence for the Amyloid Formation of a Recombinant Rab2 Isoform of Leishmania donovani.
    Roshanara, Shivani A Muthu, Gulafsha, Rati Tandon, Angamuthu Selvapandiyan, Basir Ahmad.
      BACKGROUND: The most fatal form of Visceral leishmaniasis or kala-azar is caused by the intracellular protozoan parasite Leishmania donovani. The life cycle and the infection pathway of the parasite are regulated by the small GTPase family of Rab proteins. The involvement of Rab proteins in neurodegenerative amyloidosis is implicated in protein misfolding, secretion abnormalities and dysregulation. The inter and intra-cellular shuttlings of Rab proteins are proposed to be aggregation-prone. However, the biophysical unfolding and aggregation of protozoan Rab proteins is limited. Understanding the aggregation mechanisms of Rab protein will determine their physical impact on the disease pathogenesis and individual health.OBJECTIVE: This work investigates the acidic pH-induced unfolding and aggregation of a recombinant Rab2 protein from L. donovani (rLdRab2) using multi-spectroscopic probes.
    METHODS: The acidic unfolding of rLdRab2 induced at acidic pH is characterised by intrinsic fluorescence and ANS assay, while aggregation is determined by Thioflavin-T and 90⁰ light scattering assay. Circular dichroism determined the secondary structure of monomers and aggregates. The aggregate morphology was imaged by transmission electron microscopy.
    RESULTS: rLdRab2 was modelled to be a Rab2 isoform with loose globular packing. The acidinduced unfolding of the protein is a plausible non-two-state process. At pH 2.0, a partially folded intermediate (PFI) state characterised by ~ 30 % structural loss and exposed hydrophobic core was found to accumulate. The PFI state slowly converted into well-developed protofibrils at high protein concentrations demonstrating its amyloidogenic nature. The native state of the protein was also observed to be aggregation-prone at high protein concentrations. However, it formed amorphous aggregation instead of fibrils.
    CONCLUSION: To our knowledge, this is the first study to report in vitro amyloid-like behaviour of Rab proteins in L donovani. This study provides a novel opportunity to understand the complete biophysical characteristics of Rab2 protein of the lower eukaryote, L. donovani.
    Keywords:  Recombinant Rab2; circular dichroism; intrinsic fluorescence.; protein aggregation; protein unfolding; protofibrils
    DOI:  https://doi.org/10.2174/0109298665299157240327084614
  16. Biochemistry (Mosc). 2024 Mar;89(3): 523-542
    Role of the Gut Microbiome and Bacterial Amyloids in the Development of Synucleinopathies.
    Nina P Trubitsina, Anton B Matiiv, Tatyana M Rogoza, Anna A Zudilova, Mariya D Bezgina, Galina A Zhouravleva, Stanislav A Bondarev.
      Less than ten years ago, evidence began to accumulate about association between the changes in the composition of gut microbiota and development of human synucleinopathies, in particular sporadic form of Parkinson's disease. We collected data from more than one hundred and thirty experimental studies that reported similar results and summarized the frequencies of detection of different groups of bacteria in these studies. It is important to note that it is extremely rare that a unidirectional change in the population of one or another group of microorganisms (only an elevation or only a reduction) was detected in the patients with Parkinson's disease. However, we were able to identify several groups of bacteria that were overrepresented in the patients with Parkinson's disease in the analyzed studies. There are various hypotheses about the molecular mechanisms that explain such relationships. Usually, α-synuclein aggregation is associated with the development of inflammatory processes that occur in response to the changes in the microbiome. However, experimental evidence is accumulating on the influence of bacterial proteins, including amyloids (curli), as well as various metabolites, on the α-synuclein aggregation. In the review, we provided up-to-date information about such examples.
    Keywords:  Parkinson’s disease; alpha-synuclein; amyloids; bacterial amyloids; curli; dysbiosis; microbiome; neurodegenerative diseases
    DOI:  https://doi.org/10.1134/S0006297924030118
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