bims-proned 2025-03-23 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–03–23
nine papers selected by
Verena Kohler, Umeå University

Investigating the impact of Cu2+ on α-synuclein aggregation: A single-molecule approach.
Ganglioside lipids inhibit the aggregation of the Alzheimer's amyloid-β peptide.
Diverse influences on tau aggregation and implications for disease progression.
Lysophosphatidylcholine promoting α-Synuclein aggregation in Parkinson's disease: disrupting GCase glycosylation and lysosomal α-Synuclein degradation.
Intersecting molecular pathways in Synucleinopathies and Amyloidogenesis: Exploring shared mechanisms and therapeutic potential.
Preclinical assessment of a ganglioside-targeted therapy for Parkinson's disease with the first-in-class adaptive peptide AmyP53.
Critical role of microRNAs in cellular quality control during brain aging and neurological disorders: Interplay between autophagy and proteostasis.
Enhanced alpha-synuclein pathology and exacerbated motor dysfunction in alpha-synuclein transgenic mice with autophagy deficiency.
Unravelling the amyloid aggregation mechanism of the sweet protein Monellin: Insights from circular permutated mutants.

Int J Biol Macromol. 2025 Mar 18. pii: S0141-8130(25)02713-8. [Epub ahead of print] 142161

Investigating the impact of Cu2+ on α-synuclein aggregation: A single-molecule approach.

Imad Abrao-Nemeir, Saly Charles-Achille, Bastien Cayrol, Sebastien Balme.

  Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the abnormal aggregation of α-synuclein. This study investigated the impact of Cu2+ ions on α-synuclein aggregation in oligomer distribution using two single-molecule techniques. The aggregation of α-synuclein monomers with and without Cu2+ revealed that Cu2+ accelerated the formation of ThT-positive β-sheet structured aggregates. Nanopipettes of varying diameters from to 7 to 134 nm were employed to characterize the oligomers formed during the lag phase, demonstrating that Cu2+ generated a wider range of oligomers from 10 nm3 to 20,000 nm3 over time. Confocal fluorescence spectroscopy analysis of ThT-positive fibrils in the plateau phase showed that Cu2+ induces larger oligomers and fewer in number. The introduction of preformed seeds to the control and Cu2+-containing samples further accelerated the aggregation. The combination of seeds and Cu2+ produced structurally distinct oligomers, with seeds catalyzing the formation of small oligomers that detach from the parent fibers and Cu2+, promoting the formation of larger oligomers. These results reveals that seeds and Cu2+ act synergistically, with two different aggregation pathways coexisting in the early phase, leading to an intermediate composition of fibers and clusters at the end of aggregation.

Keywords:  Alpha synuclein; Amyloid; Confocal fluorescence spectrocopy; Nanopore; Single molecule

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.142161
RSC Chem Biol. 2025 Mar 13.

Ganglioside lipids inhibit the aggregation of the Alzheimer's amyloid-β peptide.

Zenon Toprakcioglu, Akhila K Jayaram, Tuomas P J Knowles.

The aggregation of the amyloid-β (Aβ) peptides (Aβ42/Aβ40) into amyloid fibrils and plaques is one of the molecular hallmarks in dementia and Alzheimer's disease (AD). While the molecular mechanisms behind this aggregation process are not fully known, it has been shown that some biomolecules can accelerate this process whereas others can inhibit amyloid formation. Lipids, which are ubiquitously found in cell membranes, play a pivotal role in protein aggregation. Here, we investigate how ganglioside lipids, which are abundant in the brain and in neurons, can influence the aggregation kinetics of both Aβ42 and Aβ40. We employ a variety of biophysical assays to characterise the effect ganglioside lipids have on the aggregation of Aβ. Through kinetic analysis, we show that the primary nucleation rate is greatly affected by the addition of gangliosides and that these lipids impair Aβ42 aggregation, while completely inhibiting Aβ40 aggregation. Furthermore, we find that an Aβ-ganglioside complex is formed, which potentially disrupts the aggregation pathway and results in delayed kinetics. Taken together, our results provide a quantitative description of how lipid molecules such as gangliosides can inhibit the aggregation of Aβ and shed light on the key factors that control these processes. In view of the fact that declining levels of gangliosides in neurons have been associated with ageing, our findings could be instrumental towards establishing new approaches in the prevention of amyloid-β aggregation.

DOI: https://doi.org/10.1039/d4cb00189c
Genes Dev. 2025 Mar 20.

Diverse influences on tau aggregation and implications for disease progression.

Meaghan Van Alstyne, James Pratt, Roy Parker.

  Tau is an intrinsically disordered protein that accumulates in fibrillar aggregates in neurodegenerative diseases. The misfolding of tau can be understood as an equilibrium between different states and their propensity to form higher-order fibers, which is affected by several factors. First, modulation of the biochemical state of tau due to ionic conditions, post-translational modifications, cofactors, and interacting molecules or assemblies can affect the formation and structure of tau fibrils. Second, cellular processes impact tau aggregation through modulating stability, clearance, disaggregation, and transport. Third, through interactions with glial cells, the neuronal microenvironment can affect intraneuronal conditions with impacts on tau fibrilization and toxicity. Importantly, tau fibrils propagate through the brain via a "prion-like" manner, contributing to disease progression. This review highlights the biochemical and cellular pathways that modulate tau aggregation and discusses implications for pathobiology and tau-directed therapeutic approaches.

Keywords:  neurodegeneration; protein aggregation; tau; tauopathy

DOI:  https://doi.org/10.1101/gad.352551.124
NPJ Parkinsons Dis. 2025 Mar 15. 11(1): 47

Lysophosphatidylcholine promoting α-Synuclein aggregation in Parkinson's disease: disrupting GCase glycosylation and lysosomal α-Synuclein degradation.

Chunyan Mu, Kaiquan Shao, Mingyu Su, Yurong Guo, Yuxiang Qiu, Ruiao Sun, Sihan Sun, Yaoyu Sun, Chenkai Liu, Wei Wang, Xiaoling Qin, Chuanxi Tang.

In Parkinson's Disease (PD), elevated serum lysophosphatidylcholine (LPC) levels correlate with disease progression. However, the mechanisms by which abnormal LPC elevation contributes to PD-related neurotoxicity remain poorly understood. This study aims to investigate the pathogenic role of LPC in dopaminergic neuronal damage and elucidates its underlying mechanisms. Our results showed LPC induces α-synuclein aggregation, exacerbating cognitive dysfunction. LPC activates Cleaved-Caspase3 via the orphan receptor GPR35-ERK signaling pathway, inhibits GRASP65 expression, and disrupts the polarized structure of the Golgi apparatus. This disruption impairs glycosylation and function of glucocerebrosidase (GCase), preventing its transport to lysosomes and leading to glucosylceramide (GlcCer) accumulation, a scaffold for α-synuclein aggregation. LPC also disrupts the autophagolysosomal pathway and lysosomal acidification, exacerbating toxic α-synuclein accumulation. Restoring GCase glycosylation, limiting GlcCer synthesis, or blocking ERK signaling mitigates these effects. This study highlights LPC's role in promoting α-synuclein aggregation and autophagolysosomal dysfunction, advancing our understanding of PD pathology.

DOI: https://doi.org/10.1038/s41531-025-00902-7
Brain Res. 2025 Mar 14. pii: S0006-8993(25)00126-X. [Epub ahead of print] 149568

Intersecting molecular pathways in Synucleinopathies and Amyloidogenesis: Exploring shared mechanisms and therapeutic potential.

Jashanpreet Kaur, Veerta Sharma, Heena Khan, Shareen Singh, Thakur Gurjeet Singh.

  Synucleinopathies and amyloidogenic disorders are the two most prevalent neurodegenerative conditions, characterized by progressive loss of neurons and aggregation of proteins in the central nervous system. Emerging evidence suggests that despite their distinct pathological hallmarks: α-synuclein in Parkinson's disease (PD) and amyloid-β in Alzheimer's disease (AD), both disorders share common molecular pathways, including oxidative stress, neuroinflammation, misfolding/aggregation of proteins and mitochondrial dysfunction. This review explores the molecular intersections between synucleinopathies and amyloidogenesis. Furthermore, this review highlights how these pathways drive neuronal loss and suggest that targeting them could provide broad therapeutic benefits. By elucidating the shared mechanisms between PD and AD, the multi-targeted therapies could address the underlying molecular disruptions common to both disorders, offering new avenues for effective disease-modifying treatments in neurodegenerative diseases.

Keywords:  Amyloidogenesis; Neurodegeneration; Neuroinflammation; Protein misfolding; Synucleinopathies

DOI:  https://doi.org/10.1016/j.brainres.2025.149568
Sci Rep. 2025 Mar 17. 15(1): 9144

Preclinical assessment of a ganglioside-targeted therapy for Parkinson's disease with the first-in-class adaptive peptide AmyP53.

Jacques Fantini, Fodil Azzaz, Anaïs Aulas, Henri Chahinian, Nouara Yahi.

  We propose a new concept for the treatment of Parkinson's disease (PD), which considers that its root cause, α-synuclein, is an intrinsically disordered protein (IDP) difficult to target by classic approaches. Upon binding to lipid raft gangliosides, α-synuclein shifts from random coil to α-helix, forming Ca2+-permeable oligomeric pores triggering a neurotoxicity cascade. We used the α-synuclein-ganglioside interaction as guideline to design a therapeutic peptide (AmyP53) that combines the respective flexible ganglioside-binding domains of α-synuclein and Alzheimer's β-amyloid protein. AmyP53 is an adaptive peptide, the first representant of a new therapeutic class. It acts as a competitive inhibitor of α-synuclein oligomer formation in brain cell membranes and prevents subsequent downstream synaptotoxicity, including the loss of dopaminergic neurons in an animal α-synuclein injection model of PD. It is active against both wild-type and mutant forms of α-synuclein. AmyP53 is administered intranasally without side effects. This new concept "target the target (gangliosides), not the arrow (IDP)" is distinct from classic α-synuclein centric approaches that did not cure PD so far.

Keywords:  Adaptive peptide; Alzheimer; Calcium homeostasis; Ganglioside; IDP; Lipid raft; Parkinson; Pore-like annular oligomer; Synucleopathies; Therapy

DOI:  https://doi.org/10.1038/s41598-025-94148-1
Life Sci. 2025 Mar 13. pii: S0024-3205(25)00197-3. [Epub ahead of print]369 123563

Critical role of microRNAs in cellular quality control during brain aging and neurological disorders: Interplay between autophagy and proteostasis.

Rajesh Tamatta, Abhishek Kumar Singh.

  A decline in cellular quality control mechanisms is one of the processes of brain aging. Autophagy and proteostasis are two regulatory mechanisms that maintain cellular component turnover to preserve cellular homeostasis, optimal function, and neuronal health by eliminating damaged and aggregated proteins and preventing neurodegenerative disorders (NDDs). Impaired autophagy and proteostasis are significant hallmarks of aging and many age-related NDDs. MicroRNAs are noncoding RNA molecules that have recently been shown to be essential for regulating several biological processes, such as autophagy, proteostasis, cellular differentiation, and development by targeting mRNA's 3'untranslated region (3'UTR). During brain aging, miRNAs have been shown to dysregulate proteostasis and autophagy, resulting in abnormal cellular activity and protein aggregation, a characteristic of age-related NDDs. This review highlights the complex interactions of miRNAs in the orchestration of proteostasis and autophagy. This dysregulation impairs autophagic flux and proteostasis and accelerates age-related disorders, neuroinflammation, and neurodegeneration. Understanding the complex interactions among miRNAs, autophagy, and proteostasis in the aging brain is essential for novel therapeutics development for age-related NDDs.

Keywords:  Autophagy; Neurodegeneration; Neuroinflammation; Proteostasis; miRNA

DOI:  https://doi.org/10.1016/j.lfs.2025.123563
Biochem Biophys Res Commun. 2025 Feb 19. pii: S0006-291X(25)00228-1. [Epub ahead of print]758 151514

Enhanced alpha-synuclein pathology and exacerbated motor dysfunction in alpha-synuclein transgenic mice with autophagy deficiency.

Sachiko Noda, Shigeto Sato, Hodaka Yamakado, Ryosuke Takahashi, Nobutaka Hattori.

  Alpha-synuclein (α-synuclein), a key component of Lewy body pathology, is a hallmark of Parkinson's disease. In previous studies, we examined dopaminergic neuron-specific Atg7 autophagy-deficient mice and observed α-synuclein aggregation in vivo. Notably, p62 accumulation preceded synuclein deposition, resulting in the formation of inclusions containing both α-synuclein and p62. This pathological process led to dopamine neuron loss and age-related motor impairments, such as hindlimb defects in 120-week-old mice. In this study, we developed a mouse model by crossing human α-synuclein bacterial artificial chromosome transgenic mice with dopaminergic neuron-specific Atg7 conditional knockout mice to investigate these mechanisms further. The mice exhibited accelerated Lewy body-like pathology and motor dysfunction, providing additional evidence that autophagy deficiency exacerbates synuclein toxicity in vivo. Phosphorylated synuclein deposits were detected in the substantia nigra, hippocampus, and cortical regions reliant on dopaminergic pathways. Degeneration of dopaminergic neurons in the substantia nigra pars compacta was also observed, with neuron numbers declining with age. Interestingly, this mouse model displayed more severe motor deficits than Atg7 autophagy-deficient mice. This novel model offers a valuable platform for studying the interplay between α-synuclein expression, autophagy dysfunction, and neurodegeneration, as well as for testing therapeutic strategies targeting synucleinopathies. Our findings highlight the importance of aging in the manifestation of synuclein toxicity, mirroring the progression observed in patients with Parkinson's disease.

Keywords:  Atg7; Autophagy; Dopamine; Parkinson's disease; p62; α-synuclein

DOI:  https://doi.org/10.1016/j.bbrc.2025.151514
Int J Biol Macromol. 2025 Mar 19. pii: S0141-8130(25)02791-6. [Epub ahead of print] 142239

Unravelling the amyloid aggregation mechanism of the sweet protein Monellin: Insights from circular permutated mutants.

Rosanna Lucignano, Andrea Bologna, Simona Gramazio, Po-Hsun Wang, Christof Taxis, Lars-Oliver Essen, Delia Picone, Roberta Spadaccini.

  Protein amyloid aggregates, once regarded solely as pathological hallmarks of human neurodegenerative diseases, have recently gained attention for their potential in biotechnological applications. Among others, MNEI and its variants, initially developed as single-chain derivatives of the sweet protein monellin, also serve as valuable models for studying protein fibrillary aggregation. In this work, we have characterized three circular permutated mutants of MNEI obtained joining the N- and C-termini of MNEI with linkers of different length and restoring the splitting of the polypeptide chain of native monellin. All proteins are well folded but have a different propensity to form oligomeric structures in solution and aggregation rates comparable to or faster than MNEI, as indicated by Thioflavin-T binding assays. Transmission Electron Microscopy (TEM) studies indicate that only Perm1, the mutant with the longest linker, forms fibrillar aggregates. X-ray structures of the mutants show that they crystallize as domain-swapped dimers. Molecular dynamics study highlights potential hot spots controlling the ordered aggregation process of Perm1. Our data support the idea that the formation of a domain-swapped dimer does not favour the formation of fibrillar aggregates and highlight circular permutation as a valuable tool to build nanostructured biomaterials.

Keywords:  Amyloid aggregates; Circular permutation; Domain swapping; MNEI; Protein design

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.142239