bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2023‒09‒17
eight papers selected by
Verena Kohler, University of Graz

  1. J Neurochem. 2023 Sep 11.
      Protein quality control mechanisms oversee numerous aspects of protein lifetime. From the point of protein synthesis, protein homeostasis machineries take part in folding, solubilization, and/or degradation of impaired proteins. Some proteins follow an alternative path upon loss of their solubility, thus are secluded from the cytosol and form protein aggregates. Protein aggregates differ in their function and composition, rendering protein aggregation a complex phenomenon that continues to receive plenty of attention in the scientific and medical communities. Traditionally, protein aggregates have been associated with aging and a large spectrum of protein folding diseases, such as neurodegenerative diseases, type 2 diabetes, or cataract. However, a body of evidence suggests that they may act as an adaptive mechanism to overcome transient stressful conditions, serving as a sink for the removal of misfolded proteins from the cytosol or storage compartments for machineries required upon stress release. In this review, we present examples and evidence elaborating different possible roles of protein aggregation and discuss their potential roles in stress survival, aging, and disease, as well as possible anti-aggregation interventions.
    Keywords:  aging; neurodegeneration; protein aggregation; protein folding diseases; proteostasis
  2. Chempluschem. 2023 Sep 14. e202300257
      Tau and α-synuclein are proteins involved in pathologies known as tauopathies and synucleinopathies, respectively. Moreover, evidence shows that there is a crosstalk between them as is seen in the brains of individuals with sporadic neurodegenerative disorders. Based on that, we present data showing that the hydrophobic α-peptide 71VTGVTAVAQKTV82 induces the aggregation of the full-length tau fragment in the absence of heparin assessed by ThT. Moreover, AFM images reveal the presence of straight filaments and amorphous aggregates of full-length tau in the presence of the α-peptide.  Additionally, ITC experiments showed the interaction of the α-peptide with tau full-length (441),4R (244-369), and both hexapeptides 275VQIINK280 and 306VQIVYK311 through hydrophobic interactions. The Raman spectroscopy spectra showed conformational changes in the Amide region in the aggregates formed with full-length tau and α-syn peptide. Furthermore, the incubation of extracellular aggregates with N2a cells showed morphological differences in the cellular body and the nucleus. Also, the incubation of different types of aggregates in cell culture provokes the release of Lactate dehydrogenase (LDH). Altogether, we found that α-synuclein peptide can drive the aggregation of full-length tau-provoking morphological and structural changes evoking cytotoxic effects.
    Keywords:  Tau * α-syn * conformational changes * Hydrophobic interactions * cell death
  3. Neurobiol Dis. 2023 Sep 09. pii: S0969-9961(23)00300-5. [Epub ahead of print]186 106285
      Neurodegenerative disorders of aging are characterized by the progressive accumulation of proteins such as α-synuclein (α-syn) and amyloid beta (Aβ). Misfolded and aggregated α-syn has been implicated in neurological disorders such as Parkinson's disease, and Dementia with Lewy Bodies, but less so in Alzheimer's Disease (AD), despite the fact that accumulation of α-syn has been confirmed in over 50% of postmortem brains neuropathologically diagnosed with AD. To date, no therapeutic strategy has effectively or consistently downregulated α-syn in AD. Here we tested the hypothesis that by using a systemically-delivered peptide (ApoB11) bound to a modified antisense oligonucleotide against α-syn (ASO-α-syn), we can downregulate α-syn expression in an AD mouse model and improve behavioral and neuropathologic phenotypes. Our results demonstrate that monthly systemic treatment with of ApoB11:ASO α-syn beginning at 6 months of age reduces expression of α-synuclein in the brains of 9-month-old AD mice. Downregulation of α-syn led to reduction in Aβ plaque burden, prevented neuronal loss and astrogliosis. Furthermore, we found that AD mice treated with ApoB11:ASO α-syn had greatly improved hippocampal and spatial memory function in comparison to their control counterparts. Collectively, our data supports the reduction of α-syn through use of systemically-delivered ApoB11:ASO α-syn as a promising future disease-modifying therapeutic for AD.
    Keywords:  Alpha synuclein; Alzheimer's disease; Amyloid beta; Antisense oligonucleotide; Biomarkers; Comorbidity
  4. Front Mol Biosci. 2023 ;10 1155753
      Parkinson's disease is characterised by the deposition in the brain of amyloid aggregates of α-synuclein. The surfaces of these amyloid aggregates can catalyse the formation of new aggregates, giving rise to a positive feedback mechanism responsible for the rapid proliferation of α-synuclein deposits. We report a procedure to enhance the potency of a small molecule to inhibit the aggregate proliferation process using a combination of in silico and in vitro methods. The optimized small molecule shows potency already at a compound:protein stoichiometry of 1:20. These results illustrate a strategy to accelerate the optimisation of small molecules against α-synuclein aggregation by targeting secondary nucleation.
    Keywords:  Parkinson’s disease; docking; drug discovery; kinetic theory; secondary nucleation
  5. Neuromolecular Med. 2023 Sep 12.
      Parkinson's disease (PD) is a common neurodegenerative disease that is mainly in middle-aged people and elderly people, and the pathogenesis of PD is complex and diverse. The ubiquitin-proteasome system (UPS) is a master regulator of neural development and the maintenance of brain structure and function. Dysfunction of components and substrates of this UPS has been linked to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Moreover, UPS can regulate α-synuclein misfolding and aggregation, mitophagy, neuroinflammation and oxidative stress to affect the development of PD. In the present study, we review the role of several related E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) on the pathogenesis of PD such as Parkin, CHIP, USP8, etc. On this basis, we summarize the connections and differences of different E3 ubiquitin ligases in the pathogenesis, and elaborate on the regulatory progress of different DUBs on the pathogenesis of PD. Therefore, we can better understand their relationships and provide feasible and valuable therapeutic clues for UPS-related PD treatment research.
    Keywords:  Mitophagy; Parkinson's disease; Ubiquitin proteasome system
  6. bioRxiv. 2023 Aug 30. pii: 2023.08.30.555637. [Epub ahead of print]
      Background: Neurodegenerative tauopathies may progress based on seeding by pathological tau assemblies, whereby an aggregate is released from one cell, gains entry to an adjacent or connected cell, and serves as a specific template for its own replication in the cytoplasm. In vitro seeding reactions typically take days, yet seeding into the complex cytoplasmic milieu can happen within hours. A cellular machinery might regulate this process, but potential players are unknown.Methods: We used proximity labeling to identify factors that control seed amplification. We fused split-APEX2 to the C-terminus of tau repeat domain (RD) to reconstitute peroxidase activity upon seeded intracellular tau aggregation. We identified valosin containing protein (VCP/p97) 5h after seeding. Mutations in VCP underlie two neurodegenerative diseases, multisystem proteinopathy and vacuolar tauopathy, but its mechanistic role is unclear. We utilized tau biosensors, a cellular model for tau aggregation, to study the effects of VCP on tau seeding.
    Results: VCP knockdown reduced tau seeding. However, distinct chemical inhibitors of VCP and the proteasome had opposing effects on aggregation, but only when given <8h of seed exposure. ML-240 increased seeding efficiency ∼40x, whereas NMS-873 decreased seeding efficiency by 50%, and MG132 increased seeding ∼10x. We screened VCP co-factors in HEK293 biosensor cells by genetic knockout or knockdown. Reduction of ATXN3, NSFL1C, UBE4B, NGLY1, and OTUB1 decreased tau seeding, as did NPLOC4, which also uniquely increased soluble tau levels. Reduction of FAF2 and UBXN6 increased tau seeding.
    Conclusions: VCP uses distinct cofactors to determine seed replication efficiency, consistent with a dedicated cytoplasmic processing complex that directs seeds towards dissolution vs. amplification.
  7. Curr Med Chem. 2023 Sep 13.
      Parkinson's disease (PD) is a devastating neurodegenerative condition that mostly damages dopaminergic neurons in the substantia nigra and impairs human motor function. Males are more likely than females to have PD. There are two main pathways associated with PD: one involves the misfolding of α-synuclein, which causes neurodegeneration, and the other is the catalytic oxidation of dopamine via MAO-B, which produces hydrogen peroxide that can cause mitochondrial damage. Parkin (PRKN), α-synuclein (SNCA), heat shock protein (HSP), and leucine-rich repeat kinase-2 (LRRK2) are some of the target areas for genetic alterations that cause neurodegeneration in Parkinson's disease (PD). Under the impact of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is also important in Parkinson's disease (PD), inhibition of mitochondrial complex 1 results in enhanced ROS generation in neuronal cells. Natural products are still a superior option in the age of synthetic pharmaceuticals because of their lower toxicity and moderate side effects. A promising treatment for PD has been discovered using beta-carboline (also known as " β-carboline") and indole alkaloids. However, there are not many studies done on this particular topic. In the herbs containing β-carbolines and indoles, the secondary metabolites and alkaloids, β-carbolines and indoles, have shown neuroprotective and cognitive-enhancing properties. In this review, we have presented results from 18 years of research on the effects of indole and β-carboline alkaloids against oxidative stress and MAO inhibition, two key targets in PD. In the SAR analysis, the activity has been correlated with their unique structural characteristics. This study will undoubtedly aid researchers in looking for new PD treatment options.
    Keywords:  MAO-B; Parkinson’s disease; alkaloids; indole; α-synuclein.; β-carboline
  8. Nat Commun. 2023 Sep 15. 14(1): 5718
      Despite the accumulating evidence linking the development of Alzheimer's disease (AD) to the aggregation of Aβ peptides and the emergence of Aβ oligomers, the FDA has approved very few anti-aggregation-based therapies over the past several decades. Here, we report the discovery of an Aβ peptide aggregation inhibitor: an ultra-small nanodot called C3N. C3N nanodots alleviate aggregation-induced neuron cytotoxicity, rescue neuronal death, and prevent neurite damage in vitro. Importantly, they reduce the global cerebral Aβ peptides levels, particularly in fibrillar amyloid plaques, and restore synaptic loss in AD mice. Consequently, these C3N nanodots significantly ameliorate behavioral deficits of APP/PS1 double transgenic male AD mice. Moreover, analysis of critical tissues (e.g., heart, liver, spleen, lung, and kidney) display no obvious pathological damage, suggesting C3N nanodots are biologically safe. Finally, molecular dynamics simulations also reveal the inhibitory mechanisms of C3N nanodots in Aβ peptides aggregation and its potential application against AD.