bims-proned 2024-11-03 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024–11–03
seventeen papers selected by
Verena Kohler, Umeå University

Targeting Protein Aggregation in ALS.
Cholesterol Accelerates Aggregation of α-Synuclein Simultaneously Increasing the Toxicity of Amyloid Fibrils.
The small molecule ZPD-2 inhibits the aggregation and seeded polymerisation of C-terminally truncated α-Synuclein.
Short Repeat Ribonucleic Acid Reduces Cytotoxicity by Preventing the Aggregation of TDP-43 and Its 25 KDa Carboxy-Terminal Fragment.
Small Molecules, α-Synuclein Pathology, and the Search for Effective Treatments in Parkinson's Disease.
Complement Receptor 1 Is a Potential Extracerebral Factor Promoting α-Synuclein Pathology.
Elucidating ATP's role as solubilizer of biomolecular aggregate.
Distinct Effects of SARS-CoV-2 Protein Segments on Structural Stability, Amyloidogenic Potential, and α-Synuclein Aggregation.
Amyloid accelerator polyphosphate fits as the mystery density in α-synuclein fibrils.
Real-Time 3D Imaging and Inhibition Analysis of Human Serum Amyloid A Aggregations Using Quantum Dots.
Bisdemethoxycurcumin, a novel potent polyphenolic compound, effectively inhibits the formation of amyloid aggregates in ALS-associated hSOD1 mutant (L38R).
An 11-mer Synthetic Peptide Suppressing Aggregation of Aβ25-35 and Resolving Its Aggregated Form Improves Test Performance in an Aβ25-35-Induced Alzheimer's Mouse Model.
Structural basis of epitope recognition by anti-alpha-synuclein antibodies MJFR14-6-4-2.
Monitoring and analysis of mitochondrial precursor protein aggregates in the cytosol.
Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases.
α-Synuclein Strain Dynamics Correlate with Cognitive Shifts in Parkinson's Disease.
Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease.

Biomolecules. 2024 Oct 18. pii: 1324. [Epub ahead of print]14(10):

Targeting Protein Aggregation in ALS.

Michele Perni, Benedetta Mannini.

  Proteinopathies involve the abnormal accumulation of specific proteins. Maintaining the balance of the proteome is a finely regulated process managed by a complex network of cellular machinery responsible for protein synthesis, folding, and degradation. However, stress and ageing can disrupt this balance, leading to widespread protein aggregation. Currently, several therapies targeting protein aggregation are in clinical trials for ALS. These approaches mainly focus on two strategies: addressing proteins that are prone to aggregation due to mutations and targeting the cellular mechanisms that maintain protein homeostasis to prevent aggregation. This review will cover these emerging drugs. Advances in ALS research not only offer hope for better outcomes for ALS patients but also provide valuable insights and methodologies that can benefit the broader field of neurodegenerative disease drug discovery.

Keywords:  amyotrophic lateral sclerosis; clinical trials; drug discovery; inflammation; neurodegeneration; protein aggregation; protein homeostasis; therapeutics

DOI:  https://doi.org/10.3390/biom14101324
ACS Chem Neurosci. 2024 Oct 29.

Cholesterol Accelerates Aggregation of α-Synuclein Simultaneously Increasing the Toxicity of Amyloid Fibrils.

Mikhail Matveyenka, Abid Ali, Charles L Mitchell, Harris C Brown, Dmitry Kurouski.

  A hallmark of Parkinson disease (PD) is a progressive degeneration of neurons in the substantia nigra pars compacta, hypothalamus, and thalamus. Although the exact etiology of irreversible neuronal degeneration is unclear, a growing body of experimental evidence indicates that PD could be triggered by the abrupt aggregation of α-synuclein (α-Syn), a small membrane protein that is responsible for cell vesicle trafficking. Phospholipids uniquely alter the rate of α-Syn aggregation and, consequently, change the cytotoxicity of α-Syn oligomers and fibrils. However, the role of cholesterol in the aggregation of α-Syn remains unclear. In this study, we used Caenorhabditis elegans that overexpressed α-Syn to investigate the effect of low (15%), normal (30%), and high (60%) concentrations of cholesterol on α-Syn aggregation. We found that an increase in the concentration of cholesterol in diets substantially shortened the lifespan of C. elegans. Using biophysical methods, we also investigated the extent to which large unilamellar vesicles (LUVs) with low, normal, and high concentrations of cholesterol altered the rate of α-Syn aggregation. We found that only lipid membranes with a 60% concentration of cholesterol substantially accelerated the rate of protein aggregation. Cell assays revealed that α-Syn fibrils formed in the presence of LUVs with different concentrations of cholesterol exerted very similar levels of cytotoxicity to rat dopaminergic neurons. These results suggest that changes in the concentration of cholesterol in the plasma membrane, which in turn could be caused by nutritional preferences, could accelerate the onset and progression of PD.

Keywords:  Caenorhabditis elegans; ROS; cholesterol; fibrils; α-synuclein

DOI:  https://doi.org/10.1021/acschemneuro.4c00501
FEBS J. 2024 Oct 27.

The small molecule ZPD-2 inhibits the aggregation and seeded polymerisation of C-terminally truncated α-Synuclein.

Samuel Peña-Díaz, Salvador Ventura.

  Protein aggregation, particularly the formation of amyloid fibrils, is associated with numerous human disorders, including Parkinson's disease. This neurodegenerative condition is characterised by the accumulation of α-Synuclein amyloid fibrils within intraneuronal deposits known as Lewy bodies or neurites. C-terminally truncated forms of α-Synuclein are frequently observed in these inclusions in the brains of patients, and their increased aggregation propensity suggests a role in the disease's pathogenesis. This study demonstrates that the small molecule ZPD-2 acts as a potent inhibitor of both the spontaneous and seeded amyloid polimerisation of C-terminally truncated α-Synuclein by interfering with early aggregation intermediates. This dual activity positions this molecule as a promising candidate for therapeutic development in treating synucleinopathies.

Keywords:  inhibition; oligomer; protein aggregation; truncation; α‐Synuclein

DOI:  https://doi.org/10.1111/febs.17310
JACS Au. 2024 Oct 28. 4(10): 3896-3909

Short Repeat Ribonucleic Acid Reduces Cytotoxicity by Preventing the Aggregation of TDP-43 and Its 25 KDa Carboxy-Terminal Fragment.

Ai Fujimoto, Masataka Kinjo, Akira Kitamura.

TAR DNA/RNA-binding protein 43 kDa (TDP-43) proteinopathy is a hallmark of neurodegenerative disorders, such as amyotrophic lateral sclerosis, in which cytoplasmic aggregates containing TDP-43 and its C-terminal fragments, such as TDP-25, are observed in degenerative neuronal cells. However, few reports have focused on small molecules that can reduce their aggregation and cytotoxicity. Here, we show that short RNA repeats of GGGGCC and AAAAUU are aggregation suppressors of TDP-43 and TDP-25. TDP-25 interacts with these RNAs, as well as TDP-43, despite the lack of major RNA-recognition motifs using fluorescence cross-correlation spectroscopy. Expression of these RNAs significantly decreases the number of cells harboring cytoplasmic aggregates of TDP-43 and TDP-25 and ameliorates cell death by TDP-25 and mislocalized TDP-43 without altering the cellular transcriptome of molecular chaperones. Consequently, short RNA repeats of GGGGCC and AAAAUU can maintain proteostasis by preventing the aggregation of TDP-43 and TDP-25.

DOI: https://doi.org/10.1021/jacsau.4c00566
Int J Mol Sci. 2024 Oct 18. pii: 11198. [Epub ahead of print]25(20):

Small Molecules, α-Synuclein Pathology, and the Search for Effective Treatments in Parkinson's Disease.

Gian Pietro Sechi, M Margherita Sechi.

  Parkinson's disease (PD) is a progressive age-related neurodegenerative disorder affecting millions of people worldwide. Essentially, it is characterised by selective degeneration of dopamine neurons of the nigro-striatal pathway and intraneuronal aggregation of misfolded α-synuclein with formation of Lewy bodies and Lewy neurites. Moreover, specific small molecules of intermediary metabolism may have a definite pathophysiological role in PD. These include dopamine, levodopa, reduced glutathione, glutathione disulfide/oxidised glutathione, and the micronutrients thiamine and ß-Hydroxybutyrate. Recent research indicates that these small molecules can interact with α-synuclein and regulate its folding and potential aggregation. In this review, we discuss the current knowledge on interactions between α-synuclein and both the small molecules of intermediary metabolism in the brain relevant to PD, and many other natural and synthetic small molecules that regulate α-synuclein aggregation. Additionally, we analyse some of the relevant molecular mechanisms potentially involved. A better understanding of these interactions may have relevance for the development of rational future therapies. In particular, our observations suggest that the micronutrients ß-Hydroxybutyrate and thiamine might have a synergistic therapeutic role in halting or reversing the progression of PD and other neuronal α-synuclein disorders.

Keywords:  Parkinson’s disease; intermediary metabolism; small molecules; thiamine; treatment; ß-hydroxybutyrate; α-synuclein

DOI:  https://doi.org/10.3390/ijms252011198
Mol Neurobiol. 2024 Oct 29.

Complement Receptor 1 Is a Potential Extracerebral Factor Promoting α-Synuclein Pathology.

Yunying Yang, Sichun Chen, Yan Gao, Liqin Huang, Zehua Liu, Chaoyang Liu, Xin Fang, Zhentao Zhang.

  The deposition of pathological α-synuclein (α-Syn) in the central nervous system (CNS) is a hallmark of Parkinson's disease (PD). Notably, pathological α-Syn exists not only in the CNS but also in peripheral organs and body fluids in PD patients. Emerging evidence has shown the transmission of α-Syn pathology from the body to the brain. Nevertheless, the factors that drive the aggregation of peripheral α-Syn remain largely unknown. Here, we revealed that complement receptor 1 (CR1), a component of the peripheral blood system, acts as a promoter of α-Syn pathology. The transmembrane domain of CR1 (CR1-TM) exacerbates α-Syn phosphorylation and aggregation in vitro. Furthermore, intravenous injection of α-Syn fibrils induced the formation of α-Syn pathology in the brain. Co-administration of CR1-TM exacerbated α-Syn pathology induced by intravenous injection of preformed α-Syn fibrils. Our findings suggest that extracerebral factors such as CR1 can drive α-Syn pathology and serve as therapeutic targets for treating synucleinopathies.

Keywords:  Aggregation; Complement receptor 1; Phosphorylation; Seeding; α-Synuclein

DOI:  https://doi.org/10.1007/s12035-024-04561-2
Elife. 2024 Oct 30. pii: RP99150. [Epub ahead of print]13

Elucidating ATP's role as solubilizer of biomolecular aggregate.

Susmita Sarkar, Saurabh Gupta, Chiranjit Mahato, Dibyendu Das, Jagannath Mondal.

  Proteins occurring in significantly high concentrations in cellular environments (over 100 mg/ml) and functioning in crowded cytoplasm, often face the prodigious challenges of aggregation which are the pathological hallmark of aging and are critically responsible for a wide spectrum of rising human diseases. Here, we combine a joint-venture of complementary wet-lab experiment and molecular simulation to discern the potential ability of adenosine triphosphate (ATP) as solubilizer of protein aggregates. We show that ATP prevents both condensation of aggregation-prone intrinsically disordered protein Aβ40 and promotes dissolution of preformed aggregates. Computer simulation links ATP's solubilizing role to its ability to modulate protein's structural plasticity by unwinding protein conformation. We show that ATP is positioned as a superior biological solubilizer of protein aggregates over traditional chemical hydrotropes, potentially holding promises in therapeutic interventions in protein-aggregation-related diseases. Going beyond its conventional activity as energy currency, the amphiphilic nature of ATP enables its protein-specific interaction that would enhance ATP's efficiency in cellular processes.

Keywords:  ATP; condensation; intrinsically disordered protein; molecular biophysics; none; structural biology

DOI:  https://doi.org/10.7554/eLife.99150
Chembiochem. 2024 Oct 31. e202400598

Distinct Effects of SARS-CoV-2 Protein Segments on Structural Stability, Amyloidogenic Potential, and α-Synuclein Aggregation.

Vince St Dollente Mesias, Jianing Zhang, Hongni Zhu, Xin Dai, Jixi Li, Jinqing Huang.

  Amyloidosis is characterized by the abnormal accumulation of misfolded proteins, called amyloid fibrils, leading to diverse clinical manifestations. Recent studies on the amyloidogenesis of SARS-CoV‑2 protein segments have raised concerns on their potential link to post-infection neurodegeneration, however, the mechanisms remain unclear. Herein, we investigated the structure, stability, and amyloidogenic propensity of a nine-residue segment (SK9) of the SARS-CoV-2 envelope protein and their impact on neuronal protein α-synuclein (αSyn) aggregation. Specifically, the amino acid sequence of the SK9 wildtype has been modified from a basic and positively charged peptide (SFYVYSRVK), to a nearly neutral and more hydrophobic peptide (SAAVASAVK, labelled as SK9 var1), and to an acidic and positively charged peptide (SFYVYSRVK, labelled as SK9 var2). Our findings reveal that the SK9 wildtype exhibited a pronounced amyloidogenic propensity due to its disordered and unstable nature, while the SK9 variants possessed more ordered and stable structures preventing the amyloid formation. Significantly, the SK9 wildtype demonstrated distinct effect on αSyn aggregation kinetics and aggregate morphology to facilitate the formation of αSyn aggregates with enhanced resistance against enzymatic degradation. This study highlights the potential of modifying short peptide sequences to fine-tune their properties, providing insights into understanding and regulating viral-induced amyloid aggregations.

Keywords:  Amyloid Aggregation; Intrinsically Disordered Proteins; Raman Spectroscopy; SARS-CoV-2 Protein Segments; α-Synuclein

DOI:  https://doi.org/10.1002/cbic.202400598
PLoS Biol. 2024 Oct;22(10): e3002650

Amyloid accelerator polyphosphate fits as the mystery density in α-synuclein fibrils.

Philipp Huettemann, Pavithra Mahadevan, Justine Lempart, Eric Tse, Budheswar Dehury, Brian F P Edwards, Daniel R Southworth, Bikash R Sahoo, Ursula Jakob.

Aberrant aggregation of α-Synuclein is the pathological hallmark of a set of neurodegenerative diseases termed synucleinopathies. Recent advances in cryo-electron microscopy have led to the structural determination of the first synucleinopathy-derived α-Synuclein fibrils, which contain a non-proteinaceous, "mystery density" at the core of the protofilaments, hypothesized to be highly negatively charged. Guided by previous studies that demonstrated that polyphosphate (polyP), a universally conserved polyanion, significantly accelerates α-Synuclein fibril formation, we conducted blind docking and molecular dynamics simulation experiments to model the polyP binding site in α-Synuclein fibrils. Here, we demonstrate that our models uniformly place polyP into the lysine-rich pocket, which coordinates the mystery density in patient-derived fibrils. Subsequent in vitro studies and experiments in cells revealed that substitution of the 2 critical lysine residues K43 and K45 with alanine residues leads to a loss of all previously reported effects of polyP binding on α-Synuclein, including stimulation of fibril formation, change in filament conformation and stability as well as alleviation of cytotoxicity. In summary, our study demonstrates that polyP fits the unknown electron density present in in vivo α-Synuclein fibrils and suggests that polyP exerts its functions by neutralizing charge repulsion between neighboring lysine residues.

DOI: https://doi.org/10.1371/journal.pbio.3002650
Int J Mol Sci. 2024 Oct 16. pii: 11128. [Epub ahead of print]25(20):

Real-Time 3D Imaging and Inhibition Analysis of Human Serum Amyloid A Aggregations Using Quantum Dots.

Liangquan Shi, Gegentuya Huanood, Shuto Miura, Masahiro Kuragano, Kiyotaka Tokuraku.

  Serum amyloid A (SAA) is one of the most important precursor amyloid proteins discovered during the study of amyloidosis, but its underlying aggregation mechanism has not yet been well elucidated. Since SAA aggregation is a key step in the pathogenesis of AA amyloidosis, amyloid inhibitors can be used as a tool to study its pathogenesis. Previously, we reported a novel microliter-scale high-throughput screening (MSHTS) system for screening amyloid β (Aβ) aggregation inhibitors based on quantum dot (QD) fluorescence imaging technology. In this study, we report the aggregation of human SAA (hSAA) in phosphate-buffered saline, in which we successfully visualized hSAA aggregation by QD using fluorescence microscopy and confocal microscopy. Two-dimensional and three-dimensional image analyses showed that most aggregations were observed at 40 μM hSAA, which was the optimal aggregation concentration in vitro. The accuracy of this finding was verified by a Thioflavin T assay. The transmission electron microscopy results showed that QD uniformly bound to hSAA aggregation. hSAA aggregation inhibitory activity was also evaluated by rosmarinic acid (RA). The results showed that RA, which is a compound with high inhibitory activity against Aβ aggregation, also exhibited high inhibitory activity against 40 μM hSAA. These results indicate that the MSHTS system is an effective tool for visualizing hSAA aggregation and for screening highly active inhibitors.

Keywords:  quantum dot nanoprobes; rosmarinic acid; serum amyloid A

DOI:  https://doi.org/10.3390/ijms252011128
Int J Biol Macromol. 2024 Oct 24. pii: S0141-8130(24)07510-X. [Epub ahead of print]282(Pt 2): 136701

Bisdemethoxycurcumin, a novel potent polyphenolic compound, effectively inhibits the formation of amyloid aggregates in ALS-associated hSOD1 mutant (L38R).

Zeinab Haghgoo Kouhi, Bagher Seyedalipour, Saman Hosseinkhani, Mohammad Javad Chaichi.

  Protein misfolding is a biological process that leads to protein aggregation. Anomalous misfolding and aggregation of human superoxide dismutase (hSOD1) into amyloid aggregates is a characteristic feature of amyotrophic lateral sclerosis (ALS), a neurodegenerative illness. Thus, focusing on the L38R mutant may be a wise decision to comprehend the SOD1 disease process in ALS. We suggest that Bisdemethoxycurcumin (BDMC) may be a strong anti-amyloidogenic polyphenol against L38R mutant aggregation. Protein stability, hydrophobicity, and flexibility were altered when BDMC was bound to the L38R mutant, as shown by molecular dynamic (MD) simulations and molecular docking. FTIR data shows α-Helix dominance in BDMC-containing samples, with reduced β-sheet and disordered peaks, indicating the decrease of aggregate species. ThT aggregation kinetics curves show BDMC reduces L38R mutant aggregation dose-dependently, with higher BDMC concentrations yielding greater reductions. TEM images showed various quantities of amorphous aggregates, but notably, 60 μM BDMC markedly reduced aggregate density, underscoring BDMC's inhibitory effect. Hemolysis tests revealed aggregate species in BDMC-treated samples were less toxic than in L38R mutant samples alone at the same concentrations and exposure times. Overall, BDMC has substantial potential to develop highly effective inhibitors that mitigate the risk of fatal ALS.

Keywords:  Amyotrophic lateral sclerosis; Bisdemethoxycurcumin; Human superoxide dismutase 1; L38R variant; Molecular dynamics simulation

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.136701
Biomolecules. 2024 Sep 29. pii: 1234. [Epub ahead of print]14(10):

An 11-mer Synthetic Peptide Suppressing Aggregation of Aβ25-35 and Resolving Its Aggregated Form Improves Test Performance in an Aβ25-35-Induced Alzheimer's Mouse Model.

Rina Nakamura, Akira Matsuda, Youichirou Higashi, Yoshihiro Hayashi, Motomi Konishi, Motoaki Saito, Toshifumi Akizawa.

  There is a high demand for the development of drugs against Alzheimer's disease (AD), which is related to the misfolding and aggregation of Amyloid-β (Aβ), due to the increasing number of patients with AD. In our present study, we aimed to assess the aggregation inhibitory effect of various synthetic YS-peptides on Aβ25-35 to identify an applicable peptide for clinical use for AD treatment and prevention. Suppression and aggregate resolution activities of YS-peptides against Aβ25-35 were evaluated using a Thioflavin T assay and scanning electron microscopy (SEM). Structure-activity relationship studies revealed that YS-RD11 (RETLVYLTHLD) and YS-RE16 (RETLVYLTHLDYDDTE) showed suppression and aggregate-resolution activities. The effect of YS-peptides on phagocytosis in microglial cells (BV-2 cells) demonstrated that YS-RD11 and YS-RE16 activated the phagocytic ability of microglia. In the Aβ25-35-induced AD mouse model, YS-RD11 prevented and improved the deficits in short-term memory. In conclusion, YS-RD11 is a suitable candidate therapeutic drug against AD and uses a strategy similar to that used for antibodies.

Keywords:  Alzheimer’s disease; ThT assay; YS-RD11 peptide; aggregation; amyloid-β peptide

DOI:  https://doi.org/10.3390/biom14101234
NPJ Parkinsons Dis. 2024 Oct 27. 10(1): 206

Structural basis of epitope recognition by anti-alpha-synuclein antibodies MJFR14-6-4-2.

Ilva Liekniņa, Lasse Reimer, Teodors Panteļejevs, Alons Lends, Kristaps Jaudzems, Aadil El-Turabi, Hjalte Gram, Anissa Hammi, Poul Henning Jensen, Kaspars Tārs.

Alpha-synuclein (α-syn) inclusions in the brain are hallmarks of so-called Lewy body diseases. Lewy bodies contain mainly aggregated α-syn together with some other proteins. Monomeric α-syn lacks a well-defined three-dimensional structure, but it can aggregate into oligomeric and fibrillar amyloid species, which can be detected using specific antibodies. Here we investigate the aggregate specificity of monoclonal MJFR14-6-4-2 antibodies. We conclude that partial masking of epitope in unstructured monomer in combination with a high local concentration of epitopes is the main reason for MJFR14-6-4-2 selectivity towards aggregates. Based on the structural insight, we produced mutant α-syn that when fibrillated is unable to bind MJFR14-6-4-2. Using these fibrils as a tool for seeding cellular α-syn aggregation, provides superior signal/noise ratio for detection of cellular α-syn aggregates by MJFR14-6-4-2. Our data provide a molecular level understanding of specific recognition of toxic amyloid oligomers, which is critical for the development of inhibitors against synucleinopathies.

DOI: https://doi.org/10.1038/s41531-024-00822-y
Methods Enzymol. 2024 ;pii: S0076-6879(24)00356-2. [Epub ahead of print]706 287-311

Monitoring and analysis of mitochondrial precursor protein aggregates in the cytosol.

Klaudia K Maruszczak, Agnieszka Chacinska.

  The vast majority of mitochondrial precursor proteins is synthesized in the cytosol and subsequently imported into the organelle with the help of targeting signals that are present within these proteins. Disruptions in mitochondrial import will result in the accumulation of the organellar precursors in the cytosol of the cell. If mislocalized proteins exceed their critical concentrations, they become prone to aggregation. Under certain circumstances, protein aggregation becomes an irreversible process, which eventually endangers cellular health. Impairment in mitochondrial biogenesis and its effect on cellular protein homeostasis were recently linked to neurodegeneration, therefore placing this process in the center of attention. In this chapter, we are presenting a set of techniques that allows to monitor and study mitochondrial precursor protein aggregates upon mitochondrial dysfunction in the cytosol of both yeast and human cells.

Keywords:  Mitochondria; Mitochondrial dysfunction; Mitochondrial import; Protein aggregates

DOI:  https://doi.org/10.1016/bs.mie.2024.07.020
Sci Adv. 2024 Nov;10(44): eadq3539

Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases.

Arpine Sokratian, Ye Zhou, Meltem Tatli, Kevin J Burbidge, Enquan Xu, Elizabeth Viverette, Sonia Donzelli, Addison M Duda, Yuan Yuan, Huizhong Li, Samuel Strader, Nirali Patel, Lauren Shiell, Tuyana Malankhanova, Olivia Chen, Joseph R Mazzulli, Lalith Perera, Henning Stahlberg, Mario Borgnia, Alberto Bartesaghi, Hilal A Lashuel, Andrew B West.

The intricate process of α-synuclein aggregation and fibrillization holds pivotal roles in Parkinson's disease (PD) and multiple system atrophy (MSA). While mouse α-synuclein can fibrillize in vitro, whether these fibrils commonly used in research to induce this process or form can reproduce structures in the human brain remains unknown. Here, we report the first atomic structure of mouse α-synuclein fibrils, which was solved in parallel by two independent teams. The structure shows striking similarity to MSA-amplified and PD-associated E46K fibrils. However, mouse α-synuclein fibrils display altered packing arrangements, reduced hydrophobicity, and heightened fragmentation sensitivity and evoke only weak immunological responses. Furthermore, mouse α-synuclein fibrils exhibit exacerbated pathological spread in neurons and humanized α-synuclein mice. These findings provide critical insights into the structural underpinnings of α-synuclein pathogenicity and emphasize a need to reassess the role of mouse α-synuclein fibrils in the development of related diagnostic probes and therapeutic interventions.

DOI: https://doi.org/10.1126/sciadv.adq3539
bioRxiv. 2024 Oct 24. pii: 2024.10.22.619694. [Epub ahead of print]

α-Synuclein Strain Dynamics Correlate with Cognitive Shifts in Parkinson's Disease.

Kundlik Gadhave, Enquan Xu, Ning Wang, Xiaodi Zhang, Jacob Deyell, Jun Yang, Anthony Wang, Youngjae Cha, Ramhari Kumbhar, Haiqing Liu, Lili Niu, Rong Chen, Shu Zhang, Catherine C Bakker, Lingtao Jin, Yajie Liang, Mingyao Ying, Valina L Dawson, Ted M Dawson, Liana S Rosenthal, Xiaobo Mao.

α-Synuclein (α-syn) strains can serve as discriminators between Parkinson's disease (PD) from other α-synucleinopathies. The relationship between α-syn strain dynamics and clinical performance as patients transition from normal cognition (NC) to cognitive impairment (CI) is not known. Here, we show that the biophysical properties and neurotoxicity of α-syn strains change as PD cognitive status transitions from NC to mild cognitive impairment (PD-MCI) and dementia (PD-D). Both cross-sectional and longitudinal analyses reveal distinct α-syn strains in PD patients correlating to their level of cognitive impairment. This study presents evidence that individuals with PD have different α-syn strains that change in accordance with their cognitive status and highlights the potential of α-syn strain dynamics to guide future diagnosis, management, and stratification of PD patients.
One Sentence Summary: Distinct features of α-syn strains change with cognitive decline in Parkinson's disease.

DOI: https://doi.org/10.1101/2024.10.22.619694
bioRxiv. 2024 Oct 18. pii: 2024.10.16.618765. [Epub ahead of print]

Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease.

Muzi Du, Suleyman C Akerman, Charlotte M Fare, Linhao Ruan, Svetlana Vidensky, Lyudmila Mamedova, Joshua Lee, Jeffrey D Rothstein.

TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of C9ORF72 -related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer's disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.

DOI: https://doi.org/10.1101/2024.10.16.618765