bims-proned 2025-02-09 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–02–09
twenty papers selected by
Verena Kohler, Umeå University

Molecular Rotors Detect the Formation and Conversion of α-Synuclein Oligomers.
Alpha-Synuclein Fails to Form Aggregates in Endocytosis-Defective Fission Yeast Strains, ∆ myo1 and ∆ end4.
Impaired Mitochondrial Function and Ubiquitin Proteasome System Activate α-Synuclein Aggregation in Zinc-Induced Neurotoxicity: Effect of Antioxidants.
Irisin promotes autophagy and attenuates NLRP3 inflammasome activation in Parkinson's disease.
Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination.
Neuronal α-synuclein toxicity is the key driver of neurodegeneration in multiple system atrophy.
Fasudil inhibits α-synuclein aggregation through ROCK-inhibition-mediated mechanisms.
Therapeutic Potential of Arimoclomol Nanomicelles: In Vitro Impact on Alzheimer's and Parkinson's Pathology and Correlation with In Vivo Inflammatory Response.
Alpha synuclein and inflammaging.
A network aggregation model for amyloid- β dynamics and treatment of Alzheimer's diseases at the brain scale.
Refining α-synuclein seed amplification assays to distinguish Parkinson's disease from multiple system atrophy.
Development of carbazole-based molecules for inhibition of mutant hSOD1 protein aggregation in Amyotrophic Lateral Sclerosis.
Investigation of All Disease-Relevant Lysine Acetylation Sites in α-Synuclein Enabled by Non-canonical Amino Acid Mutagenesis.
Activation of α7nAch receptors ameliorates α-synuclein pathology in the brain and gut of a subacute MPTP mouse model of Parkinson's disease.
Exploring immunotherapeutic strategies for neurodegenerative diseases: a focus on Huntington's disease and Prion diseases.
USP14 is crucial for proteostasis regulation and α-synuclein degradation in human SH-SY5Y dopaminergic cells.
Unlocking Disease-Modifying Treatments for TDP-43-Mediated Neurodegeneration.
Brain network and energy imbalance in Parkinson's disease: linking ATP reduction and α-synuclein pathology.
Fibrinogen degradation products exacerbate alpha-synuclein aggregation by inhibiting autophagy via downregulation of Beclin1 in multiple system atrophy.
Beyond amyloid plaque, targeting α-synuclein in Alzheimer disease: The battle continues.

ACS Appl Mater Interfaces. 2025 Feb 05.

Molecular Rotors Detect the Formation and Conversion of α-Synuclein Oligomers.

Siân C Allerton, Marina K Kuimova, Francesco A Aprile.

  α-Synuclein is an intrinsically disordered protein that forms amyloids in Parkinson's disease. Currently, detection methods predominantly report on the formation of mature amyloids but are weakly sensitive to the early stage, toxic oligomers. Molecular rotors are fluorophores that sense changes in the viscosity of their local environment. Here, we monitor α-synuclein oligomer formation using the fluorescence lifetime of molecular rotors. We detect oligomer formation and conversion into amyloids for wild-type and two α-synuclein variants, the pathological mutant A30P and ΔP1 α-synuclein, which lacks a master regulator region of aggregation (residues 36-42). We report that A30P α-synuclein shows a rate of oligomer formation similar to that of wild-type α-synuclein, whereas ΔP1 α-synuclein shows delayed oligomer formation. Additionally, both variants demonstrate a slower conversion of oligomers into amyloids. Our method provides a quantitative approach to unveiling the complex mechanism of α-synuclein aggregation, which is key to understanding the pathology of Parkinson's disease.

Keywords:  amyloids; fluorescence lifetime; molecular rotors; oligomers; α-synuclein

DOI:  https://doi.org/10.1021/acsami.4c21710
MicroPubl Biol. 2025 ;2025

Alpha-Synuclein Fails to Form Aggregates in Endocytosis-Defective Fission Yeast Strains, ∆ myo1 and ∆ end4.

Teruaki Takasaki, Ryuga Yamada, Yoshitaka Sugimoto, Reiko Sugiura.

Alpha-Synuclein (α-Syn) is a soluble neuronal protein whose aggregation is one of the hallmarks of Parkinson's disease (PD). We previously developed a fission yeast model of PD that recapitulates α-Syn aggregation upon high-level expression of human α-Syn. Here, we show that α-Syn aggregate formation in yeast requires Myo1 and End4 , proteins essential for the early steps of endocytosis. α-Syn expression levels in Δ myo1 and ∆end4 cells were comparable to wild-type cells, suggesting that defects in endocytosis disrupt α-Syn aggregation. These findings highlight the critical role of endocytosis in α-Syn aggregation and PD pathology.

DOI: https://doi.org/10.17912/micropub.biology.001479
J Mol Neurosci. 2025 Feb 05. 75(1): 16

Impaired Mitochondrial Function and Ubiquitin Proteasome System Activate α-Synuclein Aggregation in Zinc-Induced Neurotoxicity: Effect of Antioxidants.

Garima Singh, Namrata Mittra, Chetna Singh.

  Impairment in mitochondrial function and ubiquitin-proteasome system (UPS) and alpha-synuclein (α-Syn) aggregation are implicated in Zn-induced neurotoxicity. A link among these events leading to Zn-induced neurotoxicity is not yet properly deciphered. Therefore, the study intended to check the existence of a crosstalk between the mitochondria and UPS and its further link to α-Syn aggregation. The study also aimed to investigate the efficacy of tempol, a SOD mimetic and silymarin, a natural antioxidant, against Zn-induced alterations in animals and differentiated cells. Zn reduced the locomotor activity, dopamine content and tyrosine hydroxylase (TH) expression in the exposed animals. Zn augmented the levels of mitochondrial reactive oxygen species, α-Syn and protein-ubiquitin conjugates. Mitochondrial membrane potential, adenosine triphosphate (ATP) production, UPS-associated enzymatic activities and levels of UPS subunits (SUG-1 and β-5) were attenuated in Zn-exposed animals. While Zn augmented the expression of heat shock protein 110 (HSP110), peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) and Parkin translocation, the mitochondrial PTEN-induced kinase-1 (PINK-1) level was attenuated. In addition to tempol and silymarin, a mitochondrial permeability transition pore inhibitor, cyclosporine A, also alleviated the Zn-induced changes in animals. Similar trends in a few parameters were also observed in the differentiated human neuroblastoma SH-SY-5Y cells. Besides, UPS inhibitor, MG132, enhanced Zn-induced UPS impairment, protein aggregation and mitochondrial dysfunction in differentiated cells. These results suggest that mitochondrial dysfunction triggers UPS impairment or vice versa that elevates α-Syn aggregation and consequent neuronal death. Furthermore, tempol and silymarin ameliorate the mitochondrial and UPS impairments and α-Syn aggregation thereby providing protection from Zn-induced neurotoxicity.

Keywords:  Antioxidant; Dopaminergic neurodegeneration; Mitochondrial dysfunction; Ubiquitin proteasome system; Zinc; α-synuclein aggregation

DOI:  https://doi.org/10.1007/s12031-024-02293-5
Int Immunopharmacol. 2025 Feb 05. pii: S1567-5769(25)00191-2. [Epub ahead of print]149 114201

Irisin promotes autophagy and attenuates NLRP3 inflammasome activation in Parkinson's disease.

Min Zhu, Qinyu Peng, Sheng Li, Guoxin Zhang, Zhentao Zhang.

  Parkinson's disease (PD) is characterized by the aggregation and prion-like propagation of α-synuclein (α-syn). Irisin is an exercise-induced myokine that regulates energy metabolism and exerts protective effects in PD by reducing α-syn pathology. However, the molecular mechanisms underlying the role of irisin are not fully understood. Here, we show that irisin inhibits NLRP3 inflammasome activation and promotes autophagy in cultured cells. Additionally, irisin alleviates oxidative stress and reduces cell apoptosis induced by α-syn fibrils. In a PD mouse model induced by intrastriatal injection of α-syn fibrils, irisin mitigated α-syn aggregation, neuroinflammation and neurodegeneration. These observations suggest that irisin functions as a protective mediator against α-syn pathology in PD and that irisin may serve as a potential therapeutic target for the prevention and treatment of PD.

Keywords:  Autophagy; Irisin; NLRP3; Neuroinflammation; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.intimp.2025.114201
Nat Commun. 2025 Feb 07. 16(1): 1438

Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination.

Jing Gao, Yang Liu, Chenfang Si, Rui Guo, Shouqiao Hou, Xiaosong Liu, Houfang Long, Di Liu, Daichao Xu, Zai-Rong Zhang, Cong Liu, Bing Shan, Christoph W Turck, Kaiwen He, Yaoyang Zhang.

Aspirin is a potent lysine acetylation inducer, but its impact on lysine ubiquitination and ubiquitination-directed protein degradation is unclear. Herein, we develop the reversed-pulsed-SILAC strategy to systematically profile protein degradome in response to aspirin. By integrating degradome, acetylome, and ubiquitinome analyses, we show that aspirin impairs proteasome activity to inhibit proteasomal degradation, rather than directly suppressing lysine ubiquitination. Interestingly, aspirin increases lysosomal degradation-implicated K63-linked ubiquitination. Accordingly, using the major pathological protein of Parkinson's disease (PD), α-synuclein (α-syn), as an example of protein aggregates, we find that aspirin is able to reduce α-syn in cultured cells, neurons, and PD model mice with rescued locomotor ability. We further reveal that the α-syn aggregate clearance induced by aspirin is K63-ubiquitination dependent in both cells and PD mice. These findings suggest two complementary mechanisms by which aspirin regulates the degradation of soluble and insoluble proteins, providing insights into its diverse pharmacological effects that can aid in future drug development efforts.

DOI: https://doi.org/10.1038/s41467-025-56737-6
Brain. 2025 Feb 05. pii: awaf030. [Epub ahead of print]

Neuronal α-synuclein toxicity is the key driver of neurodegeneration in multiple system atrophy.

James A Wiseman, Glenda M Halliday, Birger Victor Dieriks.

  Multiple system atrophy (MSA) is a rare, rapidly progressing neurodegenerative disorder often misdiagnosed as Parkinson's disease (PD). While both conditions share some clinical features, MSA is distinct in its pathological hallmark: oligodendroglial cytoplasmic α-synuclein (α-Syn) inclusions, known as glial cytoplasmic inclusions (GCIs). These GCIs are pathognomonic for MSA, but they do not lead to significant oligodendroglial cell loss. Instead, MSA is characterised by a substantially greater loss of non-dopaminergic neurons in the nigrostriatal and olivopontocerebellar systems compared to PD. This widespread neuronal degeneration, which is not seen to the same extent in PD, plays a critical role in MSA's clinical presentation and is important to consider if PD is to be redefined as a neuronal α-Syn disease. It also raises the question of differences in the potential toxicity of lesions in MSA and the underlying cause of neuronal death in MSA. By combining an N-terminus α-Syn antibody that reveals more α-Syn pathology and super-resolution microscopy, we identified α-Syn fibrils in MSA neurons penetrating the nucleus from the cytoplasm, leading to nuclear destruction and neuronal death. Our data indicate an early invasion of neuronal nuclei by α-Syn pathology in MSA, precipitating rapid nuclear envelope destruction, as observed through significant structural damage, including the loss of Lamin integrity. Although the progression of α-Syn pathology from the cytoplasm to the nucleus may be similar in oligodendroglia and neurons, the aggregation state of the α-Syn proteoforms involved differs as proteolytic resistance of α-Syn inclusions is significantly higher in neurons and the nucleus is destroyed. We describe the progressive impact of α-Syn nuclear pathology on MSA neurons and show that this is a more detrimental and rapid pathology driving neurodegeneration. Our data suggest that oligodendroglial inclusions contain more soluble, less toxic α-Syn proteoforms, consistent with two distinct α-Syn filaments in MSA. We propose renaming MSA as a neuronal nuclear and oligodendroglial α-synucleinopathy to better reflect these two distinct pathologies.

Keywords:  multiple system atrophy; neuronal inclusions; neuronal synucleinopathy; nuclear inclusions; oligodendroglial inclusions; α-synuclein

DOI:  https://doi.org/10.1093/brain/awaf030
Neurotherapeutics. 2025 Feb 05. pii: S1878-7479(25)00022-4. [Epub ahead of print] e00544

Fasudil inhibits α-synuclein aggregation through ROCK-inhibition-mediated mechanisms.

Lucia Lage, Ana I Rodriguez-Perez, Jose Luis Labandeira-Garcia, Antonio Dominguez-Meijide.

  ROCK inhibitors such as fasudil protected against dopaminergic degeneration and other neurodegenerative processes in several experimental models through inhibition of neuroinflammation and activation of survival signaling pathways, and clinical trials have been initiated. More recently, fasudil has been suggested to inhibit α-synuclein aggregation. However, this is controversial, particularly if it is a consequence of direct binding of the fasudil molecule to α-synuclein. We studied the mechanisms involved in the effects of fasudil on α-synuclein aggregation using the α-synuclein-T/V5-synphilin-1 model. Molecule-molecule interactions were studied using real time quaking inducing conversion (RT-QuiC). Fasudil decreased the number of cells with inclusions and the size of inclusions in dopaminergic neurons and glial cells, and inhibited α-synuclein aggregation and microglial endocytosis of aggregates. These changes were not due to changes in α-synuclein protein expression or phosphorylation and were related to ROCK inhibition rather than direct interaction with α-synuclein, as confirmed with a second ROCK inhibitor (Y27632) and ROCK gene silencing. We observed that ROCK inhibition downregulates several factors that are known to promote α-synuclein aggregation such as NADPH-oxidase-derived oxidative stress, intracellular calcium increase, and α-synuclein endocytosis, and promotes autophagy. The present results support that fasudil is a useful drug against Parkinson's disease progression. In addition to other reported neuroprotective properties, fasudil inhibits α-synuclein aggregation and microglial endocytosis of aggregates, which enhances the microglial inflammatory response. The effects of fasudil are mostly related to ROCK inhibition, which we have shown using two structurally different ROCK inhibitors and knockdown data, and further supported by using RT-QuiC.

Keywords:  Alpha-synuclein; Angiotensin; Neurodegeneration; Neuroinflammation; Parkinson; Rho-kinase

DOI:  https://doi.org/10.1016/j.neurot.2025.e00544
ACS Chem Neurosci. 2025 Feb 05.

Therapeutic Potential of Arimoclomol Nanomicelles: In Vitro Impact on Alzheimer's and Parkinson's Pathology and Correlation with In Vivo Inflammatory Response.

Isabelle Xavier-de-Britto, Natália Cristina Gomes-da-Silva, Marilia Amável Gomes Soares, Cristian Follmer, David Dabkiewicz, Luciana Magalhães Rebelo Alencar, Celso Sant'Anna, Tatiana Paula Teixeira Ferreira, Patrícia Machado Rodrigues E Silva Martins, Eduardo Ricci-Junior, Pierre Basílio Almeida Fechine, Ralph Santos-Oliveira.

  This study investigates the potential of arimoclomol-loaded nanomicelles for the treatment of neurodegenerative diseases like Alzheimer's and Parkinson's, as well as their anti-inflammatory properties. Arimoclomol, a coinducer of heat shock proteins (HSPs), has shown clinical promise in mitigating protein misfolding, a hallmark of these diseases. In this work, arimoclomol nanomicelles significantly reduced the aggregation of β-amyloid (Aβ1-42) and α-synuclein (α-syn), key pathological proteins in Alzheimer's and Parkinson's. Additionally, the nanomicelles demonstrated potent anti-inflammatory effects, reducing leukocyte and neutrophil counts in an acute inflammation model. These results suggest that arimoclomol nanomicelles could enhance clinical outcomes by targeting both neurodegenerative and inflammatory processes, offering a promising therapeutic strategy for long-term disease management.

Keywords:  drug delivery; inflammation; neurodegenerative disease

DOI:  https://doi.org/10.1021/acschemneuro.4c00734
Heliyon. 2025 Jan 30. 11(2): e41981

Alpha synuclein and inflammaging.

Geneviève L Putnam, Robert W Maitta.

  The α-synuclein protein is an established molecule in Lewy body pathology, especially Parkinson's disease (PD). While the pathological role of α-synuclein (α-syn) in PD has been well described, novel evidence may suggest that α-syn interacts with inflammasomes in response to aging. As age is an inevitable physiological state and is also considered the greatest risk factor for PD, this calls for investigation into how α-syn, aging, and PD could be linked. There is a growing amount of data regarding α-syn normal function in the body that includes involvement in cellular transport such as protein complexes assembly, vesicular trafficking, neurotransmitter release, as well as immune cell maturation. Regarding abnormal α-syn, a number of autosomal dominant mutations have been identified as causes of familial PD, however, symptomatology may not become apparent until later in life due to compensatory mechanisms in the dopaminergic response. This potentially links age-related physiological changes not only as a risk factor for PD, but for the concept of "inflammaging ". This is defined as chronic inflammation that accompanies aging observed in many neurodegenerative pathologies, that include α-syn's ability to form oligomers and toxic fibrils seen in PD. This oligomeric α-syn stimulates pro-inflammatory signals, which may worsen PD symptoms and propagate chronic inflammation. Thus, this review will explore a potential link between α-syn's role in the immune system, inflammaging, and PD.

Keywords:  Aging; Inflammaging; Inflammation; Parkinson's disease; α-synuclein

DOI:  https://doi.org/10.1016/j.heliyon.2025.e41981
J Math Biol. 2025 Feb 01. 90(2): 22

A network aggregation model for amyloid- β dynamics and treatment of Alzheimer's diseases at the brain scale.

Georgia S Brennan, Alain Goriely.

  Neurodegenerative diseases are associated with the assembly of specific proteins into oligomers and fibrillar aggregates. At the brain scale, these protein assemblies can diffuse through the brain and seed other regions, creating an autocatalytic protein progression. The growth and transport of these assemblies depend on various mechanisms that can be targeted therapeutically. Here, we use spatially-extended nucleation-aggregation-fragmentation models for the dynamics of prion-like neurodegenerative protein-spreading in the brain to study the effect of different drugs on whole-brain Alzheimer's disease progression.

Keywords:  Aggregation models; Alzheimer’s diseases; Network model; Neurodgenerative diseases; Proteinopathy

DOI:  https://doi.org/10.1007/s00285-024-02179-5
Transl Neurodegener. 2025 Feb 07. 14(1): 7

Refining α-synuclein seed amplification assays to distinguish Parkinson's disease from multiple system atrophy.

James A Wiseman, Clinton P Turner, Richard L M Faull, Glenda M Halliday, Birger Victor Dieriks.

   BACKGROUND: Parkinson's disease (PD) and multiple system atrophy (MSA) are two distinct α-synucleinopathies traditionally differentiated through clinical symptoms. Early diagnosis of MSA is problematic, and seed amplification assays (SAAs), such as real-time quaking-induced conversion (RT-QuIC), offer the potential to distinguish these diseases through their underlying α-synuclein (α-Syn) pathology and proteoforms. Currently, SAAs provide a binary result, signifying either the presence or absence of α-Syn seeds. To enhance the diagnostic potential and biological relevance of these assays, there is a pressing need to incorporate quantification and stratification of α-Syn proteoform-specific aggregation kinetics into current SAA pipelines.
METHODS: Optimal RT-QuIC assay conditions for α-Syn seeds extracted from PD and MSA patient brains were determined, and assay kinetics were assessed for α-Syn seeds from different pathologically relevant brain regions (medulla, substantia nigra, hippocampus, middle temporal gyrus, and cerebellum). The conformational profiles of disease- and region-specific α-Syn proteoforms were determined by subjecting the amplified reaction products to concentration-dependent proteolytic digestion with proteinase K.
RESULTS: Using our protocol, PD and MSA could be accurately delineated using proteoform-specific aggregation kinetics, including α-Syn aggregation rate, maximum relative fluorescence, the gradient of amplification, and core protofilament size. MSA cases yielded significantly higher values than PD cases across all four kinetic parameters in brain tissues, with the MSA-cerebellar phenotype having higher maximum relative fluorescence than the MSA-Parkinsonian phenotype. Statistical significance was maintained when the data were analysed regionally and when all regions were grouped.
CONCLUSIONS: Our RT-QuIC protocol and analysis pipeline can distinguish between PD and MSA, and between MSA phenotypes. MSA α-Syn seeds induce faster propagation and exhibit higher aggregation kinetics than PD α-Syn, mirroring the biological differences observed in brain tissue. With further validation of these quantitative parameters, we propose that SAAs could advance from a yes/no diagnostic to a theranostic biomarker that could be utilised in developing therapeutics.

Keywords:  Conformational variability; Multiple system atrophy; Parkinson’s disease; RT-QuIC; Seed amplification assays; α-Synuclein; α-Synuclein strains

DOI:  https://doi.org/10.1186/s40035-025-00469-6
Bioorg Med Chem. 2025 Jan 30. pii: S0968-0896(25)00032-X. [Epub ahead of print]120 118091

Development of carbazole-based molecules for inhibition of mutant hSOD1 protein aggregation in Amyotrophic Lateral Sclerosis.

Siddharth Gusain, Chandra Bhushan Mishra, Kajal Yadav, Meenakshi Sharma, Daman Saluja, Manisha Tiwari.

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the loss of upper and lower motor neurons. Cu/Zn superoxide dismutase (SOD1) is one of the genes associated with the familial form of the disease (fALS). The mechanism of neuron degeneration by SOD1 is not clear, it is hypothesised that there is a toxic gain of function in the protein which leads to the downstream effects. In the present study, carbazole-based molecules have been rationally designed and synthesised as potential inhibitors of mutant hSOD1 protein aggregation. SG-9 and SG-10 prevented the aggregation of all three purified mutant hSOD1 proteins. Transmission electron microscopy and dynamic light scattering experiments also revealed that co-incubation of SG-9 and SG-10 with mutant hSOD1 protein resulted in smaller and slender fibril forming. Molecules SG-9 and SG-10 did not display toxicity and prevented Neuro-2a cells expressing hSOD1 G85R protein from its associated cytotoxicity. SG-9 and SG-10 were also able to prevent the transfected cells from apoptosis and were also able to reduce ROS levels associated with hSOD1 G85R protein aggregation significantly. Therefore, novel carbazole derivatives SG-9 and SG-10 proved to be effective inhibitors of mutant hSOD1 protein aggregation and can be further utilised as lead molecules for the amelioration of mutant hSOD1 aggregation-associated ALS.

Keywords:  Amyotrophic Lateral Sclerosis; Apoptosis; Carbazole; MG-132; Protein aggregation; Superoxide dismutase 1

DOI:  https://doi.org/10.1016/j.bmc.2025.118091
bioRxiv. 2025 Jan 27. pii: 2025.01.21.634178. [Epub ahead of print]

Investigation of All Disease-Relevant Lysine Acetylation Sites in α-Synuclein Enabled by Non-canonical Amino Acid Mutagenesis.

Marie Shimogawa, Ming-Hao Li, Grace Shin Hye Park, Jennifer Ramirez, Hudson Lee, Paris R Watson, Swati Sharma, Zongtao Lin, Chao Peng, Benjamin A Garcia, David W Christianson, Elizabeth Rhoades, David Eliezer, E James Petersson.

Aggregates of α-synuclein (αS) are hallmarks of synucleinopathies, including Parkinson's Disease (PD) and Multiple System Atrophy (MSA). We have recently shown that αS lysine acetylation in the soluble monomer pool varies between healthy controls, PD, and MSA patients. To study the effects of lysine acetylation at all disease-relevant sites of αS, we first compared production of acetylated αS through either native chemical ligation or non-canonical amino acid (ncAA) mutagenesis. Since yields were comparable, ncAA mutagenesis was deemed superior for scanning many acetylation sites. We expressed and purified 12 disease-relevant variants and studied their binding to membranes as well as their aggregation propensities, and found that acetylation of lysine 12, 43, and 80 had particularly strong effects. To understand the implications for acetylation of monomeric αS found in healthy cells, we performed NMR experiments to study protein conformation and fluorescence correlation spectroscopy experiments to quantify lipid binding. We also investigated the effects of acetylation at lysine 12, 43, and 80 on fibril seeding in neurons. Collectively, our biochemical and cell biological investigations indicated that acetylation of K 80 could inhibit aggregation without conferring negative effects on monomer function in healthy cells. Therefore, we studied the structures of fibrils with K 80 acetylation through cryo-electron microscopy to uncover the structural basis for these effects. Finally, we identified inhibition of HDAC8 as a way of potentially increasing acetylation at K 80 and other inhibitory sites for therapeutic benefit.

DOI: https://doi.org/10.1101/2025.01.21.634178
Biomed Pharmacother. 2025 Feb 01. pii: S0753-3322(25)00065-4. [Epub ahead of print]184 117871

Activation of α7nAch receptors ameliorates α-synuclein pathology in the brain and gut of a subacute MPTP mouse model of Parkinson's disease.

Yea-Hyun Leem, Jung-Eun Park, Jin-Sun Park, Do-Yeon Kim, Jae-Min Park, Seong-Eun Kim, Jihee Lee Kang, Hee-Sun Kim.

  Parkinson's disease (PD) is a neurological disorder that causes a gradual decrease in mobility. Abnormal α-synuclein (α-syn) levels and aggregation contribute to PD development. The dissemination of α-synuclein pathology via the gut-brain axis has emerged as a critical aspect in α-synucleinopathies, including PD. Recently, α7 nicotinic acetylcholine receptor (α7nAchR) agonists have been proposed as promising agents for treating PD, owing to their biological properties such as anti-inflammatory effects. This study aims to investigate whether activation of α7nAchR improves α-synuclein pathology in the brain and gut of a mouse model of PD. We found that α7nAchR agonists, GTS-21 and PNU-282987, induced behavioral recovery and improved nigrostriatal dopaminergic neurotransmission in a subacute MPTP mouse model of PD. In addition, GTS-21 and PNU-282987 facilitated α-syn clearance in the brain and distal colon, as evidenced by a considerable reduction in the accumulation of pathogenic forms of α-syn. Accordingly, GTS-21 and PNU-282987 were found to promote the AMPK-mTOR autophagy signaling pathway. Furthermore, GTS-21 and PNU-282987 exerted anti-inflammatory effects, reducing the levels of proinflammatory mediators such as inducible nitric oxide synthase, interleukin-6, and tumor necrosis factor-α in both the brain and gut. To validate the specific effects of α7nAchR agonists, subacute MPTP mice were pretreated with methyllycaconitine (MLA), a selective α7nAchR antagonist before GTS-21 administration. Pretreatment with MLA abolished the GTS-21-elicited behavioral recovery, α-syn clearance, and anti-inflammatory effects in the brain and gut. Therefore, α7nAchR activation may be a potential candidate strategy for the treatment of PD by altering α-syn aggregation in the brain and gut.

Keywords:  Anti-inflammation; Gut-brain axis; Parkinson's disease; α-synuclein pathology; α7nAchR

DOI:  https://doi.org/10.1016/j.biopha.2025.117871
Acta Pharmacol Sin. 2025 Jan 31.

Exploring immunotherapeutic strategies for neurodegenerative diseases: a focus on Huntington's disease and Prion diseases.

Abhiyanta Mukherjee, Soumojit Biswas, Ipsita Roy.

  Immunotherapy has emerged as a promising therapeutic approach for the treatment of neurodegenerative disorders, which are characterized by the progressive loss of neurons and impaired cognitive functions. In this review, active and passive immunotherapeutic strategies that help address the underlying pathophysiology of Huntington's disease (HD) and prion diseases by modulating the immune system are discussed. The current landscape of immunotherapeutic strategies, including monoclonal antibodies and vaccine-based approaches, to treat these diseases is highlighted, along with their potential benefits and mechanisms of action. Immunotherapy generally works by targeting disease-specific proteins, which serve as the pathological hallmarks of these diseases. Additionally, the review addresses the challenges and limitations associated with immunotherapy. For HD, immunotherapeutic approaches focus on neutralizing the toxic effects of mutant huntingtin and tau proteins, thereby reducing neurotoxicity. Immunotherapeutic approaches targeting flanking sequences, rather than the polyglutamine tract in the mutant huntingtin protein, have yielded promising outcomes for patients with HD. In prion diseases, therapies attempt to prevent or eliminate misfolded proteins that cause neurodegeneration. The major challenge in prion diseases is immune tolerance. Approaches to overcome the highly tolerogenic nature of the prion protein have been discussed. A common hurdle in delivering antibodies is the blood‒brain barrier, and strategies that can breach this barrier are being investigated. As protein aggregation and neurotoxicity are related, immunotherapeutic strategies being developed for other neurodegenerative diseases could be repurposed to target protein aggregation in HD and prion diseases. While significant advances in this field have been achieved, continued research and development are necessary to overcome the existing limitations, which will help in shaping the future of immunotherapy as a strategy for managing neurological disorders.

Keywords:  Huntingtons disease; Prion disease; immunotherapy; protein aggregation; vaccination

DOI:  https://doi.org/10.1038/s41401-024-01455-w
Heliyon. 2025 Feb 15. 11(3): e42031

USP14 is crucial for proteostasis regulation and α-synuclein degradation in human SH-SY5Y dopaminergic cells.

Vignesh Srinivasan, Rabah Soliymani, Larisa Ivanova, Ove Eriksson, Nina Peitsaro, Maciej Lalowski, Mati Karelson, Dan Lindholm.

  Ubiquitin specific protease-14 (USP14) is critical for controlling proteostasis disturbed in human disorders, including Parkinson's disease (PD). Here we investigated USP14 in the regulation of α-synuclein (α-syn) degradation via the proteasome and autophagy. α-Syn and pS129 α-syn were elevated in USP14 gene-deleted SH-SY5Y dopaminergic cells with decreased proteasome activity. However, autophagy and coordinated lysosomal expression and regulation pathways were elevated in USP14 lacking cells with higher levels of the transcription factor TFEB. There was an increase in reactive oxidative species (ROS) and elongated mitochondria in USP14 deficient cells and counteracting oxidative stress decreased α-syn levels. Phosphoproteomics revealed that USP14 is phosphorylated at residue S143 that reduces its binding to the proteasome. Re-expression of wild-type and phospho-mimetic S143D-USP14 mutant lowered ROS and α-syn levels in USP14 lacking cells. USP14 is a promising factor to consider in PD to target α-syn through its regulation of proteasomes and oxidative stress in dopaminergic neurons.

Keywords:  Autophagy; Oxidative stress; Phosphorylation; Proteasome; USP14; pS129 α-Synuclein; α-Synuclein

DOI:  https://doi.org/10.1016/j.heliyon.2025.e42031
Bioessays. 2025 Feb 03. e202400257

Unlocking Disease-Modifying Treatments for TDP-43-Mediated Neurodegeneration.

Rebecca San Gil, Adam K Walker.

  Neurons degenerate in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causing progressive and inevitably fatal neurological decline. The best therapeutic strategies target underlying disease mediators, but after decades of intensive research, the causes of these neurodegenerative diseases remain elusive. Recently, coordinated activities of large consortia, increasing open access to large datasets, new methods such as cryo-transmission electron microscopy, and advancements in high-resolution omics technologies have offered new insights into the biology of disease that bring us closer to understanding mechanisms of neurodegeneration. In particular, improved understanding of the roles of the key pathological protein TAR DNA binding protein 43 (TDP-43) in disease has revealed intriguing new opportunities that provide hope for better diagnostic tools and effective treatments for ALS and FTD.

Keywords:  TARDBP; chaperones; frontotemporal dementia; motor neuron disease; neurodegenerative disease; proteogenomics

DOI:  https://doi.org/10.1002/bies.202400257
Front Mol Neurosci. 2024 ;17 1507033

Brain network and energy imbalance in Parkinson's disease: linking ATP reduction and α-synuclein pathology.

Hirohisa Watanabe, Sayuri Shima, Kazuya Kawabata, Yasuaki Mizutani, Akihiro Ueda, Mizuki Ito.

  Parkinson's disease (PD) involves the disruption of brain energy homeostasis. This encompasses broad-impact factors such as mitochondrial dysfunction, impaired glycolysis, and other metabolic disturbances, like disruptions in the pentose phosphate pathway and purine metabolism. Cortical hubs, which are highly connected regions essential for coordinating multiple brain functions, require significant energy due to their dense synaptic activity and long-range connections. Deficits in ATP production in PD can severely impair these hubs. The energy imbalance also affects subcortical regions, including the massive axonal arbors in the striatum of substantia nigra pars compacta neurons, due to their high metabolic demand. This ATP decline may result in α-synuclein accumulation, autophagy-lysosomal system impairment, neuronal network breakdown and accelerated neurodegeneration. We propose an "ATP Supply-Demand Mismatch Model" to help explain the pathogenesis of PD. This model emphasizes how ATP deficits drive pathological protein aggregation, impaired autophagy, and the degeneration of key brain networks, contributing to both motor and non-motor symptoms.

Keywords:  ATP metabolism; cortical hubs; energy imbalance; hypoxanthine; mitochondrial dysfunction; α-synuclein aggregation

DOI:  https://doi.org/10.3389/fnmol.2024.1507033
Neurotherapeutics. 2025 Feb 03. pii: S1878-7479(25)00016-9. [Epub ahead of print] e00538

Fibrinogen degradation products exacerbate alpha-synuclein aggregation by inhibiting autophagy via downregulation of Beclin1 in multiple system atrophy.

Huanzhu Liu, Ruoyang Yu, Muwei Zhang, Xiaoyan Zheng, Lizi Zhong, Wanlin Yang, Yuqi Luo, Zifeng Huang, Jialing Zheng, Hui Zhong, Xiaobo Wei, Wenhua Zheng, Yinghua Yu, Qing Wang.

  Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease arising from accumulation of the α-synuclein and aberrant protein clearance in oligodendrocytes. The mechanisms of autophagy involved in the progression of MSA remain poorly understood. It is reported that MSA patients have blood-brain barrier impairments, which may increase the entry of fibrinogen into the brain. However, the roles of fibrinogen and its degradation products (FDPs) on autophagy and α-synuclein accumulation in MSA remain unknown. Here, we established the MSA animal model by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) and 3-nitropropionic acid (3-NP), and cellular models by adding fibrillar α-syn into oligodendrocytes to investigate the mechanisms of FDPs on autophagy and accumulation of α-synuclein in oligodendrocytes. We found that FDPs inhibit the entry of α-synuclein into lysosomes for degradation, increasing aggregation of α-synuclein in oligodendrocytes (OLN-93). Our findings indicated that in OLN-93, FDPs inhibited the expressions of Beclin1 and Bif-1, which could promote the fusion of autophagosomes with lysosomes. Furthermore, the expression of α-synuclein was elevated in FDPs-injected mice, accompanied by an increase in the protein level of p62. We detected elevated expression of FDPs in the striatum of MSA mice. Finally, FDPs inhibited the expression of Beclin1 and Bif-1, which led to aberrant autophagic degradation and increased aggregation of α-synuclein and phospho-α-synuclein in MSA mice. Our study illustrates that FDPs can cause aggregation of α-synuclein in MSA by inhibiting Beclin1-mediated autophagy, which may exacerbate disease progression. These results provide a new therapeutic approach for MSA, that targets the inhibitory effect of FDPs on oligodendrocyte autophagy.

Keywords:  Autophagy; Beclin1; Fibrinogen; Fibrinogen degradation products; Multiple system atrophy; Oligodendrocyte

DOI:  https://doi.org/10.1016/j.neurot.2025.e00538
Ageing Res Rev. 2025 Feb 04. pii: S1568-1637(25)00030-3. [Epub ahead of print]105 102684

Beyond amyloid plaque, targeting α-synuclein in Alzheimer disease: The battle continues.

Hayder M Al-Kuraishy, Ghassan M Sulaiman, Hamdoon A Mohammed, Ali I Al-Gareeb, Ali K Albuhadily, Amer Al Ali, Mohammed H Abu-Alghayth.

  Alzheimer's disease (AD) is the most common neurodegenerative brain disease and represents the most frequent type of dementia characterized by cognitive impairment and amnesia. AD neuropathology is connected to the development of synaptic dysfunction and loss of synaptic homeostasis due to an imbalance in the production and clearance of β-amyloid (Aβ) and intracellular neurofibrillary tangles (NFTs). However, AD neuropathology is complex and may relate to the deposition of other misfolded proteins, such as alpha-synuclein (α-Syn). Of note, α-Syn, which is involved in the pathogenesis of Parkinson disease (PD) and Lewy body (LB) dementia, is also implicated in AD neuropathology. However, the potential role of α-Syn in AD neuropathology is elusive. Therefore, this review aims to discuss the pathological role of α-Syn in AD and how targeting α-Syn aggregates may be effective in treating AD.

Keywords:  Alzheimer disease; Neurodegenerative disease; Neuropathology; Pathogenesis; α-Syn; β-amyloid

DOI:  https://doi.org/10.1016/j.arr.2025.102684