bims-proned 2023-10-15 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2023‒10‒15
twelve papers selected by
Verena Kohler, Umeå University

Condensate interfaces can accelerate protein aggregation.
Aggregation, Transmission, and Toxicity of the Microtubule-Associated Protein Tau: A Complex Comprehension.
Evaluation of N- and O-Linked Indole Triazines for a Dual Effect on α-Synuclein and Tau Aggregation.
Elucidating the Role of Lipids in the Aggregation of Amyloidogenic Proteins.
TDP-43 as A Therapeutic Target in Neurodegenerative Diseases; Focusing on Motor Neuron Disease and Frontotemporal Dementia.
Neurodegenerative Disease Tauopathies.
Docosahexaenoic acid promotes vesicle clustering mediated by alpha-Synuclein via electrostatic interaction.
Frontotemporal Dementia P301L Mutation Potentiates but Is Not Sufficient to Cause the Formation of Cytotoxic Fibrils of Tau.
Readthrough isoform of aquaporin-4 (AQP4) as a therapeutic target for Alzheimer's disease and other proteinopathies.
Potential of ADAM 17 Signal Peptide To Form Amyloid Aggregates in Vitro.
Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila.
Identification of Aggregation Mechanism of Acetylated PHF6* and PHF6 Tau Peptides Based on Molecular Dynamics Simulations and Markov State Modeling.

Biophys J. 2023 Oct 12. pii: S0006-3495(23)00645-8. [Epub ahead of print]

Condensate interfaces can accelerate protein aggregation.

Chang-Hyun Choi, Daniel S W Lee, David W Sanders, Clifford P Brangwynne.

Protein aggregates, formed from the assembly of aberrant, misfolded proteins, are a hallmark of neurodegenerative diseases. Disease-associated aggregates such as mutant Huntingtin polyQ inclusions, are typically enriched in p62/SQSTM1, an oligomeric protein that binds to and sequesters aberrant proteins. p62 has been suggested to sequester proteins through formation of liquid-like biomolecular condensates, but the physical mechanisms by which p62 condensates may regulate pathological protein aggregation remain unclear. Here, we use a light-inducible biomimetic condensate system to show that p62 condensates enhance coarsening of mutant PolyQ aggregates through interface-mediated sequestration, which accelerates PolyQ accumulation into larger aggregates. However, the resulting large aggregates accumulate polyubiquitinated proteins, which depletes free p62, ultimately suppressing further p62 condensation. This dynamic interplay between interface-mediated coarsening of solid aggregates, and downstream consequences on the phase behavior of associated regulatory proteins, could contribute to the onset and progression of protein aggregation diseases.

DOI: https://doi.org/10.1016/j.bpj.2023.10.009
Int J Mol Sci. 2023 Oct 09. pii: 15023. [Epub ahead of print]24(19):

Aggregation, Transmission, and Toxicity of the Microtubule-Associated Protein Tau: A Complex Comprehension.

Jiaxin Hu, Wenchi Sha, Shuangshuang Yuan, Jiarui Wu, Yunpeng Huang.

  The microtubule-associated protein tau is an intrinsically disordered protein containing a few short and transient secondary structures. Tau physiologically associates with microtubules (MTs) for its stabilization and detaches from MTs to regulate its dynamics. Under pathological conditions, tau is abnormally modified, detaches from MTs, and forms protein aggregates in neuronal and glial cells. Tau protein aggregates can be found in a number of devastating neurodegenerative diseases known as "tauopathies", such as Alzheimer's disease (AD), frontotemporal dementia (FTD), corticobasal degeneration (CBD), etc. However, it is still unclear how the tau protein is compacted into ordered protein aggregates, and the toxicity of the aggregates is still debated. Fortunately, there has been considerable progress in the study of tau in recent years, particularly in the understanding of the intercellular transmission of pathological tau species, the structure of tau aggregates, and the conformational change events in the tau polymerization process. In this review, we summarize the concepts of tau protein aggregation and discuss the views on tau protein transmission and toxicity.

Keywords:  tau aggregates; tau toxicity; tau transmission; tauopathy

DOI:  https://doi.org/10.3390/ijms241915023
ACS Chem Neurosci. 2023 Oct 11.

Evaluation of N- and O-Linked Indole Triazines for a Dual Effect on α-Synuclein and Tau Aggregation.

Eduardo Ramirez, Susantha K Ganegamage, Sehong Min, Henika Patel, Adedayo Ogunware, Germán Plascencia-Villa, Heba Alnakhala, Kazuma Shimanaka, Arati Tripathi, Kuang-Wei Wang, Xiongwei Zhu, Jean-Christophe Rochet, Min-Hao Kuo, Scott E Counts, George Perry, Ulf Dettmer, Cristian A Lasagna-Reeves, Jessica S Fortin.

  Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder underlying dementia in the geriatric population. AD manifests by two pathological hallmarks: extracellular amyloid-β (Aβ) peptide-containing senile plaques and intraneuronal neurofibrillary tangles comprised of aggregated hyperphosphorylated tau protein (p-tau). However, more than half of AD cases also display the presence of aggregated α-synuclein (α-syn)-containing Lewy bodies. Conversely, Lewy bodies disorders have been reported to have concomitant Aβ plaques and neurofibrillary tangles. Our drug discovery program focuses on the synthesis of multitarget-directed ligands to abrogate aberrant α-syn, tau (2N4R), and p-tau (1N4R) aggregation and to slow the progression of AD and related dementias. To this end, we synthesized 11 compounds with a triazine-linker and evaluated their effectiveness in reducing α-syn, tau isoform 2N4R, and p-tau isoform 1N4R aggregation. We utilized biophysical methods such as thioflavin T (ThT) fluorescence assays, transmission electron microscopy (TEM), photoinduced cross-linking of unmodified proteins (PICUP), and M17D intracellular inclusion cell-based assays to evaluate the antiaggregation properties and cellular protection of our best compounds. We also performed disaggregation assays with isolated Aβ-plaques from human AD brains. Our results demonstrated that compound 10 was effective in reducing both oligomerization and fibril formation of α-syn and tau isoform 2N4R in a dose-dependent manner via ThT and PICUP assays. Compound 10 was also effective at reducing the formation of recombinant α-syn, tau 2N4R, and p-tau 1N4R fibrils by TEM. Compound 10 reduced the development of α-syn inclusions in M17D neuroblastoma cells and stopped the seeding of tau P301S using biosensor cells. Disaggregation experiments showed smaller Aβ-plaques and less paired helical filaments with compound 10. Compound 10 may provide molecular scaffolds for further optimization and preclinical studies for neurodegenerative proteinopathies.

Keywords:  antiaggregation compounds; hyperphosphorylated tau; paired helical filaments; tau; α-Synuclein

DOI:  https://doi.org/10.1021/acschemneuro.3c00464
Acc Chem Res. 2023 Oct 12.

Elucidating the Role of Lipids in the Aggregation of Amyloidogenic Proteins.

Dmitry Kurouski.

ConspectusThe abrupt aggregation of misfolded proteins is linked to the onset and spread of amyloidogenic diseases, including diabetes type 2, systemic amyloidosis, and Alzheimer's (AD) and Parkinson's diseases (PD). Although the exact cause of these pathological processes is unknown, a growing body of evidence suggests that amyloid diseases are triggered by misfolded or unfolded proteins, forming highly toxic oligomers. These transient species exhibit high structural and morphological heterogeneity. Protein oligomers can also propagate into β-sheet-rich filaments that braid and coil with other filaments to form amyloid fibrils and supramolecular structures with both flat and twisted morphologies. Microscopic examination of protein deposits formed in the brains of both AD and PD patients revealed the presence of fragments of lipid membranes. Furthermore, nanoscale infrared analysis of ex vivo extracted fibrils revealed the presence of lipids in their structure (Zhaliazka, K.; Kurouski, D. Protein Sci. 2023, 32, e4598). These findings demonstrated that lipid bilayers could play an important role in the aggregation of misfolded proteins.Experimental findings summarized in this Account show that (i) lipids uniquely change the aggregation rate of amyloidogenic proteins. In this case, the observed changes in the rates directly depend on the net charge of the lipid and the length and saturation of lipid fatty acids (FAs). For instance, zwitterionic phosphatidylcholine (PC) with 14:0 FAs inhibited the aggregation of insulin, lysozyme, and α-synuclein (α-Syn), whereas anionic phosphatidylserine with the same FAs dramatically accelerated the aggregation rate of these proteins (Dou, T., et al. J. Phys. Chem. Lett. 2021, 12, 4407. Matveyenka, M., et al. FASEB J. 2022, 36, e22543. Rizevsky, S., et al. J. Phys. Chem. Lett. 2022, 13, 2467). Furthermore, (ii) lipids uniquely alter the secondary structure and morphology of protein oligomers and fibrils formed in their presence. Utilization of nano-infrared spectroscopy revealed that such aggregates, as well as ex vivo extracted fibrils, possessed lipids in their structure. These findings are significant because (iii) lipids uniquely alter the toxicity of amyloid oligomers and fibrils formed in their presence. Specifically, PC lowered the toxicity of insulin and lysozyme oligomers, whereas α-Syn oligomers formed in the presence of this phospholipid were found to be significantly more toxic to rat dopaminergic cells compared to α-Syn oligomers grown in the lipid-free environment. Thus, the toxicity of protein oligomers and fibrils is directly determined by the chemical structure of the lipid and the secondary structure of amyloidogenic proteins (Dou, T., et al. J. Phys. Chem. Lett. 2021, 12, 4407. Matveyenka, M., et al. FASEB J. 2022, 36, e22543. Rizevsky, S., et al. J. Phys. Chem. Lett. 2022, 13, 2467). Experimental results discussed in this Account also suggest that amyloidogenic diseases could be caused by pathological changes in the lipid composition of both plasma and organelle membranes, which, in turn, may trigger protein aggregation that results in the formation of highly toxic oligomers and fibrils. Finally, the Account discusses the effects of polyunsaturated FAs on the aggregation properties of amyloidogenic proteins. Experimental findings reported by the author's laboratory revealed that polyunsaturated FAs drastically accelerated the aggregation rate of both insulin and α-Syn as well as strongly changed the secondary structure of amyloid fibrils formed in their presence.

DOI: https://doi.org/10.1021/acs.accounts.3c00386
Ageing Res Rev. 2023 Oct 07. pii: S1568-1637(23)00244-1. [Epub ahead of print] 102085

TDP-43 as A Therapeutic Target in Neurodegenerative Diseases; Focusing on Motor Neuron Disease and Frontotemporal Dementia.

Afshin Babazadeh, Stephanie L Rayner, Albert Lee, Roger S Chung.

  A common feature of adult-onset neurodegenerative diseases is the presence of characteristic pathological accumulations of specific proteins. These pathological protein depositions can vary in their protein composition, cell-type distribution, and intracellular (or extracellular) location. For example, abnormal cytoplasmic protein deposits which consist of the TDP-43 protein are found within motor neurons in patients with amyotrophic lateral sclerosis (ALS, a common form of motor neuron disease) and frontotemporal dementia (FTD). The presence of these insoluble intracellular TDP-43 inclusions suggests that restoring TDP-43 homeostasis represents a potential therapeutical strategy, which has been demonstrated in alleviating neurodegenerative symptoms in cell and animal models of ALS/FTD. We have reviewed the mechanisms that lead to disrupted TDP-43 homeostasis and discussed how small molecule-based therapies could be applied in modulating these mechanisms. This review covers recent advancements and challenges in small molecule-based therapies that could be used to clear pathological forms of TDP-43 through various protein homeostasis mechanisms and advance the way towards finding effective therapeutical drug discoveries for neurodegenerative diseases characterized by TDP-43 proteinopathies, especially ALS and FTD. We also consider the wider insight of these therapeutic strategies for other neurodegenerative diseases.

Keywords:  ALS; FTD; Motor Neuron Disease; Protein Degradation; Small Molecule; TDP-43

DOI:  https://doi.org/10.1016/j.arr.2023.102085
Annu Rev Pathol. 2023 Oct 13.

Neurodegenerative Disease Tauopathies.

Benjamin C Creekmore, Ryohei Watanabe, Edward B Lee.

Tauopathies are a diverse group of progressive and fatal neurodegenerative diseases characterized by aberrant tau inclusions in the central nervous system. Tau protein forms pathologic fibrillar aggregates that are typically closely associated with neuronal cell death, leading to varied clinical phenotypes including dementia, movement disorders, and motor neuron disease. In this review, we describe the clinicopathologic features of tauopathies and highlight recent advances in understanding the mechanisms that lead to spread of pathologic aggregates through interconnected neuronal pathways. The cell-to-cell propagation of tauopathy is then linked to posttranslational modifications, tau fibril structural variants, and the breakdown of cellular protein quality control. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 19 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-pathmechdis-051222-120750
Eur Phys J E Soft Matter. 2023 Oct 12. 46(10): 96

Docosahexaenoic acid promotes vesicle clustering mediated by alpha-Synuclein via electrostatic interaction.

Owen Tyoe, Chinta Aryal, Jiajie Diao.

α-Synuclein (α-Syn) is an intrinsically disordered protein whose aggregation is associated with Parkinson's disease, dementia, and other neurodegenerative diseases known as synucleinopathies. However, the functional role of α-Syn is still unclear, although it has been shown to be involved in the regulation of neurotransmitter release via the interaction with synaptic vesicles (SVs), vesicle clustering, and SNARE complex assembly. Fatty acids have significant occupancy in synaptic vesicles; and recent studies suggest the interaction of fatty acids with α-Syn affect the formation of (pathological) aggregates, but it is less clear how fatty acids affects the functional role of α-Syn including α-Syn-membrane interactions, in particular with (SV-like) vesicles. Here, we report the concentration dependent effect of docosahexaenoic acid (DHA) in synaptic-like vesicle clustering via α-Syn interaction. Through molecular dynamics simulation, we revealed that DHA promoted vesicle clustering is due to the electrostatic interaction between DHA in the membrane and the N-terminal region of α-Syn. Moreover, this increased electrostatic interaction arises from a change in the macroscopic properties of the protein-membrane interface induced by (preferential solvation of) DHA. Our results provide insight as to how DHA regulates vesicle clustering mediated by α-Syn and may further be useful to understand its physiological as well as pathological role. Description: In physiological environments, α-Synuclein (α-Syn) localizes at nerve termini and synaptic vesicles and interacts with anionic phospholipid membranes to promote vesicle clustering. Docosahexaenoic acid (DHA) increases binding affinity between α-Syn and lipid membranes by increasing electrostatic interaction energy through modulating the local and global membrane environment and conformational properties of α-Syn.

DOI: https://doi.org/10.1140/epje/s10189-023-00353-z
Int J Mol Sci. 2023 Oct 08. pii: 14996. [Epub ahead of print]24(19):

Frontotemporal Dementia P301L Mutation Potentiates but Is Not Sufficient to Cause the Formation of Cytotoxic Fibrils of Tau.

Kuang-Wei Wang, Gary Zhang, Min-Hao Kuo.

  The P301L mutation in tau protein is a prevalent pathogenic mutation associated with neurodegenerative frontotemporal dementia, FTD. The mechanism by which P301L triggers or facilitates neurodegeneration at the molecular level remains unclear. In this work, we examined the effect of the P301L mutation on the biochemical and biological characteristics of pathologically relevant hyperphosphorylated tau. Hyperphosphorylated P301L tau forms cytotoxic aggregates more efficiently than hyperphosphorylated wildtype tau or unphosphorylated P301L tau in vitro. Mechanistic studies establish that hyperphosphorylated P301L tau exacerbates endoplasmic reticulum (ER) stress-associated gene upregulation in a neuroblastoma cell line when compared to wildtype hyperphosphorylated tau treatment. Furthermore, the microtubule cytoskeleton is severely disrupted following hyperphosphorylated P301L tau treatment. A hyperphosphorylated tau aggregation inhibitor, apomorphine, also inhibits the harmful effects caused by P301L hyperphosphorylated tau. In short, the P301L single mutation within the core repeat domain of tau renders the underlying hyperphosphorylated tau more potent in eliciting ER stress and cytoskeleton damage. However, the P301L mutation alone, without hyperphosphorylation, is not sufficient to cause these phenotypes. Understanding the conditions and mechanisms whereby selective mutations aggravate the pathogenic activities of tau can provide pivotal clues on novel strategies for drug development for frontotemporal dementia and other related neurodegenerative tauopathies, including Alzheimer's disease.

Keywords:  Alzheimer’s disease; P301L; apomorphine; frontotemporal dementia; hyperphosphorylated tau; tauopathy

DOI:  https://doi.org/10.3390/ijms241914996
Alzheimers Res Ther. 2023 Oct 11. 15(1): 170

Readthrough isoform of aquaporin-4 (AQP4) as a therapeutic target for Alzheimer's disease and other proteinopathies.

Pablo Mohaupt, Jérôme Vialaret, Christophe Hirtz, Sylvain Lehmann.

  The glymphatic system is a crucial component in preserving brain homeostasis by facilitating waste clearance from the central nervous system (CNS). Aquaporin-4 (AQP4) water channels facilitate the continuous interchange between cerebrospinal fluid and brain interstitial fluid by convective flow movement. This flow is responsible for guiding proteins and metabolites away from the CNS. Proteinopathies are neurological conditions characterized by the accumulation of aggregated proteins or peptides in the brain. In Alzheimer's disease (AD), the deposition of amyloid-β (Aβ) peptides causes the formation of senile plaques. This accumulation has been hypothesized to be a result of the imbalance between Aβ production and clearance. Recent studies have shown that an extended form of AQP4 increases Aβ clearance from the brain. In this mini-review, we present a summary of these findings and explore the potential for future therapeutic strategies aiming to boost waste clearance in AD.

Keywords:  Alzheimer’s; Aquaporin-4; Protein aggregation; Proteinopathies; Therapeutic target; Waste clearance

DOI:  https://doi.org/10.1186/s13195-023-01318-2
ACS Chem Neurosci. 2023 Oct 06.

Potential of ADAM 17 Signal Peptide To Form Amyloid Aggregates in Vitro.

Taniya Bhardwaj, Rajanish Giri.

  ADAM 17, a disintegrin and metalloproteinase 17 belonging to the adamalysin protein family, is a Zn2+-dependent type-I transmembrane α-secretase protein. As a major sheddase, ADAM 17 acts as an indispensable regulator of chief cellular events and controls diverse cytokines, adhesion molecules, and growth factors. The signal peptide (residues 1-17) of ADAM 17 targets the protein to the secretory pathway and gets cleaved off afterward. No other function is documented for the ADAM 17 signal peptide (ADAM 17-SP) inside the cells. Here, we have taken a reductionist approach to understand the biophysical properties of ADAM 17-SP. Aiming to understand the possibility of aggregation, we found several aggregation-prone segments in the signal peptide. We performed in vitro experiments to show that the signal peptide forms amyloid-like aggregates in buffered conditions. We also studied its aggregation in the presence of sodium tripolyphosphate and heparin to correlate with the cellular conditions, as these biomolecules are naturally present inside cells. Further, we performed seeding experiments to observe the possibility of ADAM 17-SP aggregate interaction with the Aβ42 peptide. The results suggest that its seeds escalate the aggregation kinetics of the Aβ42 peptide and form heteromeric aggregates with it. We believe this finding could further intensify the aggregation studies on other signal peptides and shed light on the potential role of these segments other than signaling.

Keywords:  Aβ42; coaggregation; heparin; polyphosphates; self-seeding; β-Amyloids

DOI:  https://doi.org/10.1021/acschemneuro.3c00424
Front Aging Neurosci. 2023 ;15 1223911

Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila.

Jonathan R Roth, Ruan Carlos Macedo de Moraes, Brittney P Xu, Savannah R Crawley, Malghalara A Khan, Girish C Melkani.

  Huntington's disease (HD) is a neurodegenerative disease characterized by movement and cognitive dysfunction. HD is caused by a CAG expansion in exon 1 of the HTT gene that leads to a polyglutamine (PQ) repeat in the huntingtin protein, which aggregates in the brain and periphery. Previously, we used Drosophila models to determine that Htt-PQ aggregation in the heart causes shortened lifespan and cardiac dysfunction that is ameliorated by promoting chaperonin function or reducing oxidative stress. Here, we further study the role of neuronal mutant huntingtin and how it affects peripheral function. We overexpressed normal (Htt-PQ25) or expanded mutant (Htt-PQ72) exon 1 of huntingtin in Drosophila neurons and found that mutant huntingtin caused age-dependent Htt-PQ aggregation in the brain and could cause a loss of synapsin. To determine if this neuronal dysfunction led to peripheral dysfunction, we performed a negative geotaxis assay to measure locomotor performance and found that neuronal mutant huntingtin caused an age-dependent decrease in locomotor performance. Next, we found that rapamycin reduced Htt-PQ aggregation in the brain. These results demonstrate the role of neuronal Htt-PQ in dysfunction in models of HD, suggest that brain-periphery crosstalk could be important to the pathogenesis of HD, and show that rapamycin reduces mutant huntingtin aggregation in the brain.

Keywords:  Drosophila; Htt-polyQ; Huntington’s disease; aggregation; locomotion; neurodegeneration; rapamycin

DOI:  https://doi.org/10.3389/fnagi.2023.1223911
ACS Chem Neurosci. 2023 Oct 13.

Identification of Aggregation Mechanism of Acetylated PHF6* and PHF6 Tau Peptides Based on Molecular Dynamics Simulations and Markov State Modeling.

Syed Jawad Ali Shah, Qianqian Zhang, Jingjing Guo, Hongli Liu, Huanxiang Liu, Jordi Villà-Freixa.

  The microtubule-associated protein tau (MAPT) has a critical role in the development and preservation of the nervous system. However, tau's dysfunction and accumulation in the human brain can lead to several neurodegenerative diseases, such as Alzheimer's disease, Down's syndrome, and frontotemporal dementia. The microtubule binding (MTB) domain plays a significant, important role in determining the tau's pathophysiology, as the core of paired helical filaments PHF6* (275VQIINK280) and PHF6 (306VQIVYK311) of R2 and R3 repeat units, respectively, are formed in this region, which promotes tau aggregation. Post-translational modifications, and in particular lysine acetylation at K280 of PHF6* and K311 of PHF6, have been previously established to promote tau misfolding and aggregation. However, the exact aggregation mechanism is not known. In this study, we established an atomic-level nucleation-extension mechanism of the separated aggregation of acetylated PHF6* and PHF6 hexapeptides, respectively, of tau. We show that the acetylation of the lysine residues promotes the formation of β-sheet enriched high-ordered oligomers. The Markov state model analysis of ac-PHF6* and ac-PHF6 aggregation revealed the formation of an antiparallel dimer nucleus which could be extended from both sides in a parallel manner to form mixed-oriented and high-ordered oligomers. Our study describes the detailed mechanism for acetylation-driven tau aggregation, which provides valuable insights into the effect of post-translation modification in altering the pathophysiology of tau hexapeptides.

Keywords:  Markov state model; PHF6; PHF6*; Tau; acetylation; aggregation; molecular dynamics simulations

DOI:  https://doi.org/10.1021/acschemneuro.3c00578