bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2023–12–17
twelve papers selected by
Verena Kohler, Umeå University
  1. Gut mucosal cells transfer α-synuclein to the vagus nerve.
  2. A glimpse into the structural properties of α-synuclein oligomers.
  3. Pathogenic Impact of Fatty Acid-Binding Proteins in Parkinson's Disease-Potential Biomarkers and Therapeutic Targets.
  4. Stabilization challenges and aggregation in protein-based therapeutics in the pharmaceutical industry.
  5. A Biomimetic Multiparametric Assay to Characterise Anti-Amyloid Drugs.
  6. Sobetirome rescues α-synuclein-mediated demyelination in an in vitro model of multiple system atrophy.
  7. A conformationally-locked p-hydroxybenzylidene imidazolinone derivative for detecting Aβ42 aggregation.
  8. Characterizing cannabis-prevalent terpenes for neuroprotection reveal a role for α and β-pinenes in mitigating amyloid β-evoked neurotoxicity and aggregation in vitro.
  9. Intraneuronal β-amyloid impaired mitochondrial proteostasis through the impact on LONP1.
  10. Lifestyle strategies to promote proteostasis and reduce the risk of Alzheimer's disease and other proteinopathies.
  11. The ubiquitin thioesterase YOD1 ameliorates mutant Huntingtin induced pathology in Drosophila.
  12. The Protective Mechanism of TFAM on Mitochondrial DNA and its Role in Neurodegenerative Diseases.
  1. JCI Insight. 2023 Dec 08. pii: e172192. [Epub ahead of print]8(23):
    Gut mucosal cells transfer α-synuclein to the vagus nerve.
    Rashmi Chandra, Arpine Sokratian, Katherine R Chavez, Stephanie King, Sandip M Swain, Joshua C Snyder, Andrew B West, Rodger A Liddle.
      Epidemiological and histopathological findings have raised the possibility that misfolded α-synuclein protein might spread from the gut to the brain and increase the risk of Parkinson's disease. Although past experimental studies in mouse models have relied on gut injections of exogenous recombinant α-synuclein fibrils to study gut-to-brain α-synuclein transfer, the possible origins of misfolded α-synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of intestinal mucosa express α-synuclein. Here, we employed mouse intestinal organoids expressing human α-synuclein to observe the transfer of α-synuclein protein from epithelial cells in organoids to cocultured nodose neurons devoid of α-synuclein. In mice expressing human α-synuclein, but no mouse α-synuclein, α-synuclein fibril-templating activity emerged in α-synuclein-seeded fibril aggregation assays in intestine, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human α-synuclein expression to intestinal epithelial cells, α-synuclein fibril-templating activity transfered to the vagus nerve and dorsal motor nucleus. Subdiaphragmatic vagotomy prior to induction of α-synuclein expression in intestinal epithelial cells effectively protected the hindbrain from emergence of α-synuclein fibril-templating activity. Overall, these findings highlight a potential non-neuronal source of fibrillar α-synuclein protein that might arise in gut mucosal cells.
    Keywords:  Gastroenterology; Neuroscience; Parkinson disease
    DOI:  https://doi.org/10.1172/jci.insight.172192
  2. Biofactors. 2023 Dec 08.
    A glimpse into the structural properties of α-synuclein oligomers.
    Jaime Santos, Irantzu Pallarès, Salvador Ventura.
      α-Synuclein (αS) aggregation is the main neurological hallmark of a group of debilitating neurodegenerative disorders, collectively referred to as synucleinopathies, of which Parkinson's disease is the most prevalent. αS oligomers formed during the initial stages of aggregation are considered key pathogenic drivers of disease onset and progression, standing as privileged targets for therapeutic intervention and diagnosis. However, the structure of αS oligomers and the mechanistic basis of oligomer to fibril conversion are yet poorly understood, thereby precluding the rational formulation of strategies aimed at targeting oligomeric species. In this review, we delve into the recent advances in the structural and mechanistic characterization of αS oligomers. We also discuss how these advances are transforming our understanding of these elusive species and paving the way for oligomer-targeting therapeutics and diagnosis.
    Keywords:  Parkinson's disease; amyloid; oligomers; protein aggregation; α-Synuclein
    DOI:  https://doi.org/10.1002/biof.2021
  3. Int J Mol Sci. 2023 Dec 01. pii: 17037. [Epub ahead of print]24(23):
    Pathogenic Impact of Fatty Acid-Binding Proteins in Parkinson's Disease-Potential Biomarkers and Therapeutic Targets.
    Ichiro Kawahata, Kohji Fukunaga.
      Parkinson's disease is a neurodegenerative condition characterized by motor dysfunction resulting from the degeneration of dopamine-producing neurons in the midbrain. This dopamine deficiency gives rise to a spectrum of movement-related symptoms, including tremors, rigidity, and bradykinesia. While the precise etiology of Parkinson's disease remains elusive, genetic mutations, protein aggregation, inflammatory processes, and oxidative stress are believed to contribute to its development. In this context, fatty acid-binding proteins (FABPs) in the central nervous system, FABP3, FABP5, and FABP7, impact α-synuclein aggregation, neurotoxicity, and neuroinflammation. These FABPs accumulate in mitochondria during neurodegeneration, disrupting their membrane potential and homeostasis. In particular, FABP3, abundant in nigrostriatal dopaminergic neurons, is responsible for α-synuclein propagation into neurons and intracellular accumulation, affecting the loss of mesencephalic tyrosine hydroxylase protein, a rate-limiting enzyme of dopamine biosynthesis. This review summarizes the characteristics of FABP family proteins and delves into the pathogenic significance of FABPs in the pathogenesis of Parkinson's disease. Furthermore, it examines potential novel therapeutic targets and early diagnostic biomarkers for Parkinson's disease and related neurodegenerative disorders.
    Keywords:  Parkinson’s disease; biomarkers; dementia with Lewy bodies; dopaminergic neurons; early diagnostic techniques; fatty acid-binding protein; mitochondria; therapeutic target; tyrosine hydroxylase; α-synuclein
    DOI:  https://doi.org/10.3390/ijms242317037
  4. RSC Adv. 2023 Dec 08. 13(51): 35947-35963
    Stabilization challenges and aggregation in protein-based therapeutics in the pharmaceutical industry.
    Mahdie Rahban, Faizan Ahmad, Mieczyslaw A Piatyszek, Thomas Haertlé, Luciano Saso, Ali Akbar Saboury.
      Protein-based therapeutics have revolutionized the pharmaceutical industry and become vital components in the development of future therapeutics. They offer several advantages over traditional small molecule drugs, including high affinity, potency and specificity, while demonstrating low toxicity and minimal adverse effects. However, the development and manufacturing processes of protein-based therapeutics presents challenges related to protein folding, purification, stability and immunogenicity that should be addressed. These proteins, like other biological molecules, are prone to chemical and physical instabilities. The stability of protein-based drugs throughout the entire manufacturing, storage and delivery process is essential. The occurrence of structural instability resulting from misfolding, unfolding, and modifications, as well as aggregation, poses a significant risk to the efficacy of these drugs, overshadowing their promising attributes. Gaining insight into structural alterations caused by aggregation and their impact on immunogenicity is vital for the advancement and refinement of protein therapeutics. Hence, in this review, we have discussed some features of protein aggregation during production, formulation and storage as well as stabilization strategies in protein engineering and computational methods to prevent aggregation.
    DOI:  https://doi.org/10.1039/d3ra06476j
  5. Int J Mol Sci. 2023 Nov 30. pii: 16982. [Epub ahead of print]24(23):
    A Biomimetic Multiparametric Assay to Characterise Anti-Amyloid Drugs.
    Willy Smeralda, Marc Since, Sophie Corvaisier, Dimitri Fayolle, Julien Cardin, Sylvain Duprey, Jean-Pierre Jourdan, Christophe Cullin, Aurélie Malzert-Freon.
      Alzheimer's disease (AD) is the most widespread form of senile dementia worldwide and represents a leading socioeconomic problem in healthcare. Although it is widely debated, the aggregation of the amyloid β peptide (Aβ) is linked to the onset and progression of this neurodegenerative disease. Molecules capable of interfering with specific steps in the fibrillation process remain of pharmacological interest. To identify such compounds, we have set up a small molecule screening process combining multiple experimental methods (UV and florescence spectrometry, ITC, and ATR-FTIR) to identify and characterise potential modulators of Aβ1-42 fibrillation through the description of the biochemical interactions (molecule-membrane Aβ peptide). Three known modulators, namely bexarotene, Chicago sky blue and indomethacin, have been evaluated through this process, and their modulation mechanism in the presence of a biomembrane has been described. Such a well-adapted physico-chemical approach to drug discovery proves to be an undeniable asset for the rapid characterisation of compounds of therapeutic interest for Alzheimer's disease. This strategy could be adapted and transposed to search for modulators of other amyloids such as tau protein.
    Keywords:  Alzheimer’s disease; Chicago sky blue; bexarotene; drug discovery; indomethacin; liposomes; β-amyloïd
    DOI:  https://doi.org/10.3390/ijms242316982
  6. Eur J Neurosci. 2023 Dec 12.
    Sobetirome rescues α-synuclein-mediated demyelination in an in vitro model of multiple system atrophy.
    Lisa Mészáros, Marcus Himmler, Yanni Schneider, Philipp Arnold, Frank Dörje, Dirk W Schubert, Jürgen Winkler.
      Multiple system atrophy (MSA) is a rare and rapidly progressive atypical parkinsonian disorder characterized by oligodendroglial cytoplasmic inclusions containing α-synuclein (α-syn), demyelination, inflammation and neuronal loss. To date, no disease-modifying therapy is available. Targeting α-syn-driven oligodendroglial dysfunction and demyelination presents a potential therapeutic approach for restricting axonal dysfunction, neuronal loss and disease progression. The present study investigated the promyelinogenic potential of sobetirome, a blood-brain barrier permeable and central nervous system selective thyromimetic in the context of an in vitro MSA model. Oligodendrocyte precursor cells (OPCs) were obtained from transgenic mice overexpressing human α-syn specifically in oligodendrocytes (MBP29 mouse line), a well-described MSA model, and non-transgenic littermates. mRNA and protein expression analyses revealed a substantial rescue effect of sobetirome on myelin-specific proteins in control and α-syn overexpressing oligodendrocytes. Furthermore, myelination analysis using nanofibres confirmed that sobetirome increases both the length and number of myelinated segments per oligodendrocyte in primary murine α-syn overexpressing oligodendrocytes and their respective control. These results suggest that sobetirome may be a promising thyromimetic compound targeting an important neuropathological hallmark of MSA.
    Keywords:  MSA; myelin; oligodendrocytes; sobetirome; thyromimetics; α-synuclein
    DOI:  https://doi.org/10.1111/ejn.16215
  7. Bioorg Med Chem Lett. 2023 Dec 06. pii: S0960-894X(23)00454-7. [Epub ahead of print]98 129576
    A conformationally-locked p-hydroxybenzylidene imidazolinone derivative for detecting Aβ42 aggregation.
    Anyang Sun, Han Sun, Gulziba Anwar, Xiuhong Lu, Jinwu Yan.
      Alzheimer's disease (AD) is a common type of neurodegenerative disease, which can only be symptomatically relieved but does not yet have a cure. Among the different Aβ species, amyloid-β 42 (Aβ42) aggregates are proposed to be more neurotoxic than that of Aβ40, and oligomeric Aβ42 is thought to play a harmful role in the pathophysiology of AD. Therefore, the detection of Aβ42 aggregation is very meaningful in the AD field. We herein report a conformationally-locked p- hydroxybenzylidene imidazolinone derivative, BDI, which exhibits selectivity and specificity towards Aβ42 aggregation and remarkable fluorescent enhancement with a large Stokes shift (more than 100 nm). In the fluorescent co-localization study, BDI can sensitively detect a large population of Aβ42 aggregation over that of Aβ40 in the brain tissues of AD transgenic mouse models. Therefore, this new probe could provide a useful tool for the rapid detection of important Aβ species in AD.
    Keywords:  Alzheimer’s disease; Aβ(42) aggregation; Beta-amyloid; Fluorescent probe
    DOI:  https://doi.org/10.1016/j.bmcl.2023.129576
  8. Neurotoxicology. 2023 Dec 07. pii: S0161-813X(23)00169-9. [Epub ahead of print]100 16-24
    Characterizing cannabis-prevalent terpenes for neuroprotection reveal a role for α and β-pinenes in mitigating amyloid β-evoked neurotoxicity and aggregation in vitro.
    John Staton Laws, Scott D Smid.
       BACKGROUND: Cannabis sativa L. (C. sativa) can efficiently synthesize of over 200 terpenes, including monoterpenes, sesquiterpenes and triterpenes that may contribute to the known biological activities of phytocannabinoids of relevance for the burgeoning access to medicinal cannabis formulations globally; however, to date have been uncharacterized. We assessed twelve predominant terpenes in C. sativa for neuroprotective and anti-aggregative properties in semi-differentiated PC12 neuronal cell line that is robust and validated as a cell model responsive to amyloid β (Aβ1-42) protein exposure and oxidative stress.
    METHODS: Cell viability was assessed biochemically using the MTT assay in the presence of myrcene, β-caryophyllene, terpinolene, limonene, linalool, humulene, α-pinene, nerolidol, β-pinene, terpineol, citronellol and friedelin (1-200 μM) for 24 hr. Sub-toxic threshold test concentrations of each terpene were then applied to cells, alone or with concomitant incubation with the lipid peroxidant tert-butyl hyrdroperoxide (t-BHP; 0-250 μM) or amyloid β (Aβ1-42; 0-1 μM) to assess neuroprotective effects. Direct effects of each terpene on Aβ fibril formation and aggregation were also evaluated using the Thioflavin T (ThT) fluorometric kinetic assay and transmission electron microscopy (TEM) to visualize fibril and aggregate morphology.
    RESULTS: Terpenes were intrinsically benign to PC12 cells up to 50 μM, with higher concentrations of β-caryophyllene, humulene and nerolidol inducing some loss of PC12 cell viability. No significant protective effects of terpenes were observed following t-BHP (0-200 µM) administration, with some enhanced toxicity instead demonstrated from both β-caryophyllene and humulene treatment (each at 50 µM). α-pinene and β-pinene demonstrated a significant neuroprotective effect against amyloid β exposure. α-pinene, β-pinene, terpineol, terpinolene and friedelin were associated with a variable inhibition of Aβ1-42 fibril and aggregate density.
    CONCLUSIONS: The outcomes of this study underline a neuroprotective role of α-pinene and β-pinene against Aβ-mediated neurotoxicity associated with an inhibition of Aβ1-42 fibrilization and density. This demonstrates the bioactive potential of selected terpenes for consideration in the development of medicinal cannabis formulations targeting neurodegenerative diseases.
    Keywords:  Amyloid β; Cannabis; Neuroprotection; α-pinene; β-pinene
    DOI:  https://doi.org/10.1016/j.neuro.2023.12.004
  9. Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2316823120
    Intraneuronal β-amyloid impaired mitochondrial proteostasis through the impact on LONP1.
    Wenzhang Wang, Xiaopin Ma, Sabina Bhatta, Changjuan Shao, Fanpeng Zhao, Hisashi Fujioka, Sandy Torres, Fengqin Wu, Xiongwei Zhu.
      Mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial proteostasis regulated by chaperones and proteases in each compartment of mitochondria is critical for mitochondrial function, and it is suspected that mitochondrial proteostasis deficits may be involved in mitochondrial dysfunction in AD. In this study, we identified LONP1, an ATP-dependent protease in the matrix, as a top Aβ42 interacting mitochondrial protein through an unbiased screening and found significantly decreased LONP1 expression and extensive mitochondrial proteostasis deficits in AD experimental models both in vitro and in vivo, as well as in the brain of AD patients. Impaired METTL3-m6A signaling contributed at least in part to Aβ42-induced LONP1 reduction. Moreover, Aβ42 interaction with LONP1 impaired the assembly and protease activity of LONP1 both in vitro and in vivo. Importantly, LONP1 knockdown caused mitochondrial proteostasis deficits and dysfunction in neurons, while restored expression of LONP1 in neurons expressing intracellular Aβ and in the brain of CRND8 APP transgenic mice rescued Aβ-induced mitochondrial deficits and cognitive deficits. These results demonstrated a critical role of LONP1 in disturbed mitochondrial proteostasis and mitochondrial dysfunction in AD and revealed a mechanism underlying intracellular Aβ42-induced mitochondrial toxicity through its impact on LONP1 and mitochondrial proteostasis.
    Keywords:  Alzheimer’s disease; Aβ42; LONP1; mitochondrial dysfunction; protein aggregate
    DOI:  https://doi.org/10.1073/pnas.2316823120
  10. Ageing Res Rev. 2023 Dec 07. pii: S1568-1637(23)00321-5. [Epub ahead of print] 102162
    Lifestyle strategies to promote proteostasis and reduce the risk of Alzheimer's disease and other proteinopathies.
    Michael F Almeida, Karen L G Farizatto, Renato S Almeida, Ben A Bahr.
      Unhealthy lifestyle choices, poor diet, and aging can have negative influences on cognition, gradually increasing the risk for mild cognitive impairment (MCI) and the continuum comprising early dementia. Aging is the greatest risk factor for age-related dementias such as Alzheimer's disease, and the aging process is known to be influenced by life events that can positively or negatively affect age-related diseases. Remarkably, life experiences that make the brain vulnerable to dementia, such as seizure episodes, neurotoxin exposures, metabolic disorders, and trauma-inducing events (e.g. traumatic injuries or mild neurotrauma from a fall or blast exposure), have been associated with negative effects on proteostasis and synaptic integrity. Functional compromise of the autophagy-lysosomal pathway, a major contributor to proteostasis, has been implicated in Alzheimer's disease, Parkinson's disease, obesity-related pathology, Huntington's disease, as well as in synaptic degeneration which is the best correlate of cognitive decline. Correspondingly, pharmacological and non-pharmacological strategies that positively modulate lysosomal proteases are recognized as synaptoprotective through degradative clearance of pathogenic proteins. Here, we discuss life-associated vulnerabilities that influence key hallmarks of brain aging and the increased burden of age-related dementias. Additionally, we discuss exercise and diet among the lifestyle strategies that regulate proteostasis as well as synaptic integrity, leading to evident prevention of cognitive deficits during brain aging in pre-clinical models.
    Keywords:  brain aging; cognition; lysosomal proteases; synapses
    DOI:  https://doi.org/10.1016/j.arr.2023.102162
  11. Sci Rep. 2023 Dec 11. 13(1): 21951
    The ubiquitin thioesterase YOD1 ameliorates mutant Huntingtin induced pathology in Drosophila.
    Anita Farkas, Nóra Zsindely, Gábor Nagy, Levente Kovács, Péter Deák, László Bodai.
      Huntington's disease (HD) is a neurodegenerative disorder caused by a dominant gain-of-function mutation in the huntingtin gene, resulting in an elongated polyglutamine repeat in the mutant Huntingtin (mHtt) that mediates aberrant protein interactions. Previous studies implicated the ubiquitin-proteasome system in HD, suggesting that restoring cellular proteostasis might be a key element in suppressing pathology. We applied genetic interaction tests in a Drosophila model to ask whether modulating the levels of deubiquitinase enzymes affect HD pathology. By testing 32 deubiquitinase genes we found that overexpression of Yod1 ameliorated all analyzed phenotypes, including neurodegeneration, motor activity, viability, and longevity. Yod1 did not have a similar effect in amyloid beta overexpressing flies, suggesting that the observed effects might be specific to mHtt. Yod1 overexpression did not alter the number of mHtt aggregates but moderately increased the ratio of larger aggregates. Transcriptome analysis showed that Yod1 suppressed the transcriptional effects of mHtt and restored the expression of genes involved in neuronal plasticity, vesicular transport, antimicrobial defense, and protein synthesis, modifications, and clearance. Furthermore, Yod1 overexpression in HD flies leads to the upregulation of genes involved in transcriptional regulation and synaptic transmission, which might be part of a response mechanism to mHtt-induced stress.
    DOI:  https://doi.org/10.1038/s41598-023-49241-8
  12. Mol Neurobiol. 2023 Dec 12.
    The Protective Mechanism of TFAM on Mitochondrial DNA and its Role in Neurodegenerative Diseases.
    Ying Song, Wenjun Wang, Beibei Wang, Qiwen Shi.
      Mitochondrial transcription factor A (TFAM) is a mitochondrial protein encoded by nuclear genes and transported from the cytoplasm to the mitochondria. TFAM is essential for the maintenance, expression, and delivery of mitochondrial DNA (mtDNA) and can regulate the replication and transcription of mtDNA. TFAM is associated with the formation of mtDNA nucleomimetic structures, mtDNA repair, and mtDNA stability. However, the mechanism by which TFAM protects mtDNA is still being studied. This review provides a summary of the protective mechanism of TFAM on mtDNA including the discrete regulatory effects of TFAM acetylation and phosphorylation on mtDNA, the regulation of Ca2+ levels by TFAM to activate transcription in mitochondria, and the increased binding of TFAM to mtDNA damage hot spots. This review also discusses the association between TFAM and some neurodegenerative diseases.
    Keywords:  Mitochondria; Mitochondrial DNA; Mitochondrial transcription factor A; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s12035-023-03841-7
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