bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2023‒12‒10
nine papers selected by
Verena Kohler, Umeå University

  1. Mol Neurobiol. 2023 Dec 07.
      Accumulation of misfolded proteins compromises overall cellular health and fitness. The failure to remove misfolded proteins is a critical reason for their unwanted aggregation in dense cellular protein pools. The accumulation of various inclusions serves as a clinical feature for neurodegenerative diseases. Previous findings suggest that different cellular compartments can store these abnormal inclusions. Studies of transgenic mice and cellular models of neurodegenerative diseases indicate that depleted chaperone capacity contributes to the aggregation of damaged or aberrant proteins, which consequently disturb proteostasis and cell viability. However, improving these abnormal proteins' selective elimination is yet to be well understood. Still, molecular strategies that can promote the effective degradation of abnormal proteins without compromising cellular viability are unclear. Here, we reported that the trehalose treatment elevates endogenous proteasome levels and enhances the activities of the proteasome. Trehalose-mediated proteasomal activation elevates the removal of both bona fide misfolded and various neurodegenerative disease-associated proteins. Our current study suggests that trehalose may retain a proteasome activation potential, which seems helpful in the solubilization of different mutant misfolded proteins, improving cell viability. These results reveal a possible molecular approach to reduce the overload of intracellular misfolded proteins, and such cytoprotective functions may play a critical role against protein conformational diseases.
    Keywords:  Aberrant proteins; Diseases; Neurodegeneration; Proteasome; Proteasome activator; Trehalose
  2. Eur J Med Chem. 2023 Nov 23. pii: S0223-5234(23)00932-7. [Epub ahead of print]264 115965
      Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the accumulation of α-synuclein (α-Syn) aggregates. However, there are currently no effective therapies for PD. Brazilin, an inhibitor of α-Syn aggregation, is unstable and toxic. Therefore, we have developed and synthesized derivatives of brazilin. One of these derivatives, called brazilin-7-acetate (B-7-A), has shown reduced toxicity and a stronger effect on inhibiting α-Syn aggregation. It showed that B-7-A prevented the formation of α-Syn fibers and disrupted existing fibers in a dosage-dependent manner. Additionally, B-7-A significantly reduced the cytotoxicity of α-Syn aggregates and alleviated oxidative stress in PC12 cells. The beneficial effects of B-7-A were also confirmed using the Caenorhabditis elegans model. These effects included preventing the accumulation of α-Syn clumps, improving behavior disorder, increasing lifespan, reducing oxidative stress, and protecting against lipid oxidation and loss. Finally, B-7-A showed good ADMET properties in silico. Based on these findings, B-7-A exhibits potential as a prospective treatment for PD.
    Keywords:  Aggregation; Brazilin-7-acetate; Caenorhabditis elegans; Inhibitor; Oxidative stress; Parkinson's disease; α-synuclein
  3. BBA Adv. 2023 ;4 100110
      Synucleinopathies like Parkinson's disease are neurodegenerative diseases which are associated with the deposition of fibrillar aggregates of the endogenous protein α-synuclein (α-syn). The inhibition of the elongation of α-syn fibrils is of great scientific interest and an option in the design of therapeutic strategies. Previously, we developed a disulfide-containing mutant of α-syn, called CC48, which inhibits fibril elongation by blocking of fibril ends. Surprisingly, wildtype (WT) α-syn molecules supported the blocked state, and a fusion of CC48 with WT α-syn, denoted WT-CC48, exhibited increased inhibitory potential. Here, we studied which regions of WT-CC48 are responsible for the strong inhibitory effect. To this end, we investigated a set of truncated versions of WT-CC48 by kinetic elongation assays, density gradient centrifugation, and atomic force microscopy. We show that in both the WT and the CC48 part of the fusion construct the hairpin region (residue 32-60) and NAC region (61-95), but not N- and C-terminal regions, are required for strong inhibition of fibril elongation. The required regions correspond to the segments forming the β-sheet core of α-syn fibrils. As α-syn fibrils typically consist of two protofilaments, the dimeric construct WT-CC48 provides the critical regions sufficient to cover the full β-sheetcore interface exposed at the fibril end, which can explain its high inhibitory efficiency. We suggest a mechanistic model of CC48-mediated inhibition of fibril elongation in which CC48 and WT α-syn cooperatively form an oligomer-like cap at the amyloid fibril end.
    Keywords:  Amyloids; Elongation; Fibril polymorphs; Fibrillation; Mechanism of inhibition; α-Synuclein
  4. Neural Regen Res. 2024 Jul 01. 19(7): 1463-1472
      ABSTRACT: α-Synuclein is a protein that mainly exists in the presynaptic terminals. Abnormal folding and accumulation of α-synuclein are found in several neurodegenerative diseases, including Parkinson's disease. Aggregated and highly phosphorylated α-synuclein constitutes the main component of Lewy bodies in the brain, the pathological hallmark of Parkinson's disease. For decades, much attention has been focused on the accumulation of α-synuclein in the brain parenchyma rather than considering Parkinson's disease as a systemic disease. Recent evidence demonstrates that, at least in some patients, the initial α-synuclein pathology originates in the peripheral organs and spreads to the brain. Injection of α-synuclein preformed fibrils into the gastrointestinal tract triggers the gut-to-brain propagation of α-synuclein pathology. However, whether α-synuclein pathology can occur spontaneously in peripheral organs independent of exogenous α-synuclein preformed fibrils or pathological α-synuclein leakage from the central nervous system remains under investigation. In this review, we aimed to summarize the role of peripheral α-synuclein pathology in the pathogenesis of Parkinson's disease. We also discuss the pathways by which α-synuclein pathology spreads from the body to the brain.
  5. Neural Regen Res. 2024 Jul 01. 19(7): 1489-1498
      ABSTRACT: Alzheimer's disease is the most prevalent neurodegenerative disease affecting older adults. Primary features of Alzheimer's disease include extracellular aggregation of amyloid-β plaques and the accumulation of neurofibrillary tangles, formed by tau protein, in the cells. While there are amyloid-β-targeting therapies for the treatment of Alzheimer's disease, these therapies are costly and exhibit potential negative side effects. Mounting evidence suggests significant involvement of tau protein in Alzheimer's disease-related neurodegeneration. As an important microtubule-associated protein, tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth. In fact, clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-β in the brain. Various therapeutic strategies targeting tau protein have begun to emerge, and are considered possible methods to prevent and treat Alzheimer's disease. Specifically, abnormalities in post-translational modifications of the tau protein, including aberrant phosphorylation, ubiquitination, small ubiquitin-like modifier (SUMO)ylation, acetylation, and truncation, contribute to its microtubule dissociation, misfolding, and subcellular missorting. This causes mitochondrial damage, synaptic impairments, gliosis, and neuroinflammation, eventually leading to neurodegeneration and cognitive deficits. This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer's disease and discusses tau-targeted treatment of Alzheimer's disease.
  6. ACS Chem Neurosci. 2023 Dec 05.
      Abnormal cytosolic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is observed in multiple diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease. Previous studies have shown that TDP-43307-319 located at the C-terminal of TDP-43 can form higher-order oligomers and fibrils. Of particular interest are the hexamers that adopt a cylindrin structure that has been strongly correlated to neurotoxicity. In this study, we use the joint pharmacophore space (JPS) model to identify and generate potential TDP-43 inhibitors. Five JPS-designed molecules are evaluated using both experimental and computational methods: ion mobility mass spectrometry, thioflavin T fluorescence assay, circular dichroism spectroscopy, atomic force microscopy, and molecular dynamics simulations. We found that all five molecules can prevent the amyloid fibril formation of TDP-43307-319, but their efficacy varies significantly. Furthermore, among the five molecules, [AC0101] is the most efficient in preventing the formation of higher-order oligomers and dissociating preformed higher-order oligomers. Molecular dynamics simulations show that [AC0101] both is the most flexible and forms the most hydrogen bonds with the TDP-43307-319 monomer. The JPS-designed molecules can insert themselves between the β-strands in the hexameric cylindrin structure of TDP-43307-319 and can open its structure. Possible mechanisms for JPS-designed molecules to inhibit and dissociate TDP-43307-319 oligomers on an atomistic scale are proposed.
    Keywords:  ALS; TDP-43; amyloid oligomers; ion mobility mass spectrometry; small molecule inhibitors
  7. ACS Chem Neurosci. 2023 Dec 05.
      Amyloid β peptide (Aβ) is the crucial protein component of extracellular plaques in Alzheimer's disease. The plaques also contain gangliosides lipids, which are abundant in membranes of neuronal cells and in cell-derived vesicles and exosomes. When present at concentrations above its critical micelle concentration (cmc), gangliosides can occur as mixed micelles. Here, we study the coassembly of the ganglioside GM1 and the Aβ peptides Aβ40 and 42 by means of microfluidic diffusional sizing, confocal microscopy, and cryogenic transmission electron microscopy. We also study the effects of lipid-peptide interactions on the amyloid aggregation process by fluorescence spectroscopy. Our results reveal coassembly of GM1 lipids with both Aβ monomers and Aβ fibrils. The results of the nonseeded kinetics experiments show that Aβ40 aggregation is delayed with increasing GM1 concentration, while that of Aβ42 is accelerated. In seeded aggregation reactions, the addition of GM1 leads to a retardation of the aggregation process of both peptides. Thus, while the effect on nucleation differs between the two peptides, GM1 may inhibit the elongation of both types of fibrils. These results shed light on glycolipid-peptide interactions that may play an important role in Alzheimer's pathology.
    Keywords:  GM1 micelle; amyloid β; coassembly; kinetics; microfluidic diffusional sizing; microscopy
  8. Brain Res Bull. 2023 Dec 01. pii: S0361-9230(23)00260-5. [Epub ahead of print] 110835
      The pathological features of Alzheimer's disease (AD), a progressive neurodegenerative disorder, include the deposition of extracellular amyloid beta (Aβ) plaques and intracellular tau neurofibrillary tangles. A decline in cognitive ability is related to the accumulation of Aβ in patients with AD. Autophagy, which is a primary intracellular mechanism for degrading aggregated proteins and damaged organelles, plays a crucial role in AD. In this review, we summarize the most recent research progress regarding the process of autophagy and the effect of autophagy on Aβ. We further discuss some typical monomers of natural products that contribute to the clearance of Aβ by autophagy, which can alleviate AD. This provides a new perspective for the application of autophagy modulation in natural product therapy for AD.
    Keywords:  Alzheimer's disease; amyloid beta; autophagy; natural products
  9. Bioorg Med Chem. 2023 Nov 30. pii: S0968-0896(23)00386-3. [Epub ahead of print]97 117538
      Alzheimer's disease (AD) is a devastating neurodegenerative condition with complex pathophysiology. Aggregated amyloid beta (Aβ) peptide plaques and higher concentrations of bio-metals such as copper (Cu), zinc (Zn), and iron (Fe) are the most significant hallmarks of AD observed in the brains of AD patients. Therefore simultaneous inhibition of Aβ peptide aggregation and reduction of metal stress may serve as an effective therapeutic approach for treating Alzheimer's disease. A series of bifunctional dipeptides bearing squaramide backbone were synthesized and investigated for their ability to chelate metal ions and prevent Aβ peptide aggregation. Dipeptides with Valine (V) and Threonine (T) substitutions at the C-terminus exhibited preferential chelation with Cu(II), Zn(II), and Fe(III) metal ions in the presence of other metal ions. They were also found to inhibit the aggregation of Aβ peptide in-vitro. A further molecular dynamics (MD) simulation study demonstrated that these two dipeptides interact with the Aβ peptide in the hydrophobic core (KLVFF) region. Circular dichroism (CD) study revealed slight conformational change in the Aβ peptide upon the interactions with dipeptides. Apart from metal chelation and inhibition of Aβ peptide aggregation, the selected dipeptides were found to possess anti-oxidant properties. Therefore, the squaramide backbone-modified dipeptides may serve as an active bifunctional scaffold towards the development of new chemical entities for the treatment of Alzheimer's disease.
    Keywords:  Alzhiemer's disease (AD); Anti-oxidant; Aβ aggregation inhibitor; Bifunctional backbone modified dipeptide; Metal chelator; Squaramides