bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2021–11–28
nineteen papers selected by
Rich Giadone, Harvard University
  1. Molecular mechanisms of heat shock factor 1 regulation.
  2. Kinetic monitoring of neuronal stress response to proteostasis dysfunction.
  3. The IRE1/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism.
  4. Shining a light on autophagy in neurodegenerative diseases.
  5. The Unfolded Protein Response as a Guardian of the Secretory Pathway.
  6. A Perspective on the Potential Involvement of Impaired Proteostasis in Neuropsychiatric Disorders.
  7. With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage.
  8. An allosteric inhibitor of bacterial Hsp70 chaperone potentiates antibiotics and mitigates resistance.
  9. The Cytotoxicity and Clearance of Mutant Huntingtin and Other Misfolded Proteins.
  10. The increase of α-synuclein and alterations of dynein in A53T transgenic and aging mouse.
  11. O-GlcNAcylation in health and neurodegenerative diseases.
  12. Proteostasis regulated by testis-specific ribosomal protein RPL39L maintains mouse spermatogenesis.
  13. Association between Sleep, Alzheimer's, and Parkinson's Disease.
  14. Structural and Computational Study of the GroEL-Prion Protein Complex.
  15. Artificial intelligence powers protein-folding predictions.
  16. An atlas of protein turnover rates in mouse tissues.
  17. Examining the Toxicity of α-Synuclein in Neurodegenerative Disorders.
  18. BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis.
  19. Prion protein complexed to a DNA aptamer induce behavioral and synapse dysfunction in mice.
  1. Trends Biochem Sci. 2021 Nov 19. pii: S0968-0004(21)00230-9. [Epub ahead of print]
    Molecular mechanisms of heat shock factor 1 regulation.
    Szymon W Kmiecik, Matthias P Mayer.
      To thrive and to fulfill their functions, cells need to maintain proteome homeostasis even in the face of adverse environmental conditions or radical restructuring of the proteome during differentiation. At the center of the regulation of proteome homeostasis is an ancient transcriptional mechanism, the so-called heat shock response (HSR), orchestrated in all eukaryotic cells by heat shock transcription factor 1 (Hsf1). As Hsf1 is implicated in aging and several pathologies like cancer and neurodegenerative disorders, understanding the regulation of Hsf1 could open novel therapeutic opportunities. In this review, we discuss the regulation of Hsf1's transcriptional activity by multiple layers of control circuits involving Hsf1 synthesis and degradation, conformational rearrangements and post-translational modifications (PTMs), and molecular chaperones in negative feedback loops.
    Keywords:  Hsf1; Hsp70; chaperones; heat shock response; protein homeostasis; transcription regulation
    DOI:  https://doi.org/10.1016/j.tibs.2021.10.004
  2. Mol Cell Neurosci. 2021 Nov 17. pii: S1044-7431(21)00095-6. [Epub ahead of print]118 103682
    Kinetic monitoring of neuronal stress response to proteostasis dysfunction.
    Angel J Santiago-Lopez, Ken Berglund, Robert E Gross, Claire-Anne N Gutekunst.
      Proteostasis dysfunction and activation of the unfolded protein response (UPR) are characteristic of all major neurodegenerative diseases. Nevertheless, although the UPR and proteostasis dysfunction has been studied in great detail in model organisms like yeast and mammalian cell lines, it has not yet been examined in neurons. In this study, we applied a viral vector-mediated expression of a reporter protein based on a UPR transcription factor, ATF4, and time-lapse fluorescent microscopy to elucidate how mouse primary neurons respond to pharmacological and genetic perturbations to neuronal proteostasis. In in vitro models of endoplasmic reticulum (ER) stress and proteasome inhibition, we used the ATF4 reporter to reveal the time course of the neuronal stress response relative to neurite degeneration and asynchronous cell death. We showed how potential neurodegenerative disease co-factors, ER stress and mutant α-synuclein overexpression, impacted neuronal stress response and overall cellular health. This work therefore introduces a viral vector-based reporter that yields a quantifiable readout suitable for non-cell destructive kinetic monitoring of proteostasis dysfunction in neurons by harnessing ATF4 signaling as part of the UPR activation.
    Keywords:  Alpha-synuclein; Integrated stress response; Neurodegeneration; Proteostasis; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.mcn.2021.103682
  3. Elife. 2021 Nov 23. pii: e73215. [Epub ahead of print]10
    The IRE1/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism.
    Anirban Roy, Meiricris Tomaz da Silva, Raksha Bhat, Kyle R Bohnert, Takao Iwawaki, Ashok Kumar.
      Skeletal muscle regeneration is regulated by coordinated activation of multiple signaling pathways activated in both injured myofibers and satellite cells. The unfolded protein response (UPR) is a major mechanism that detects and alleviates protein-folding stresses in ER. However, the role of individual arms of the UPR in skeletal muscle regeneration remain less understood. In the present study, we demonstrate that IRE1α (also known as ERN1) and its downstream target, XBP1, are activated in skeletal muscle of mice upon injury. Myofiber-specific ablation of IRE1 or XBP1 in mice diminishes skeletal muscle regeneration that is accompanied with reduced number of satellite cells and their fusion to injured myofibers. Ex vivo cultures of myofiber explants demonstrate that ablation of IRE1α reduces the proliferative capacity of myofiber-associated satellite cells. Myofiber-specific deletion of IRE1α dampens Notch signaling and canonical NF-kB pathway in skeletal muscle of mice. Our results also demonstrate that targeted ablation of IRE1α reduces skeletal muscle regeneration in the mdx mice, a model of Duchenne muscular dystrophy. Collectively, our results reveal that the IRE1α-mediated signaling promotes muscle regeneration through augmenting the proliferation of satellite cells in a cell non-autonomous manner.
    Keywords:  cell biology; mouse; regenerative medicine; stem cells
    DOI:  https://doi.org/10.7554/eLife.73215
  4. J Biol Chem. 2021 Nov 18. pii: S0021-9258(21)01246-1. [Epub ahead of print] 101437
    Shining a light on autophagy in neurodegenerative diseases.
    Aswathy Chandran, Jean-Christophe Rochet.
      Small-molecule modulators of autophagy have been widely investigated as potential therapies for neurodegenerative diseases. In a recent issue of JBC, Safren et al. described a novel assay that uses a photoconvertible fusion protein to identify compounds that alter autophagic flux. Autophagy inducers identified using this assay were found to either alleviate or exacerbate neurotoxicity in different cellular models of amyotrophic lateral sclerosis, challenging the notion that autophagy stimulation can be used as a one-size-fits-all therapy for neurodegenerative disease.
    DOI:  https://doi.org/10.1016/j.jbc.2021.101437
  5. Cells. 2021 Oct 31. pii: 2965. [Epub ahead of print]10(11):
    The Unfolded Protein Response as a Guardian of the Secretory Pathway.
    Toni Radanović, Robert Ernst.
      The endoplasmic reticulum (ER) is the major site of membrane biogenesis in most eukaryotic cells. As the entry point to the secretory pathway, it handles more than 10,000 different secretory and membrane proteins. The insertion of proteins into the membrane, their folding, and ER exit are affected by the lipid composition of the ER membrane and its collective membrane stiffness. The ER is also a hotspot of lipid biosynthesis including sterols, glycerophospholipids, ceramides and neural storage lipids. The unfolded protein response (UPR) bears an evolutionary conserved, dual sensitivity to both protein-folding imbalances in the ER lumen and aberrant compositions of the ER membrane, referred to as lipid bilayer stress (LBS). Through transcriptional and non-transcriptional mechanisms, the UPR upregulates the protein folding capacity of the ER and balances the production of proteins and lipids to maintain a functional secretory pathway. In this review, we discuss how UPR transducers sense unfolded proteins and LBS with a particular focus on their role as guardians of the secretory pathway.
    Keywords:  ATF6; ER; IRE1; PERK; UPR; hydrophobic mismatch; lipid bilayer stress; membrane stiffness; membrane thickness; proteotoxic stress; secretory pathway
    DOI:  https://doi.org/10.3390/cells10112965
  6. Biol Psychiatry. 2021 Sep 14. pii: S0006-3223(21)01590-0. [Epub ahead of print]
    A Perspective on the Potential Involvement of Impaired Proteostasis in Neuropsychiatric Disorders.
    Kelvin K Hui, Ryo Endo, Akira Sawa, Motomasa Tanaka.
      Recent genetic approaches have demonstrated that genetic factors contribute to the pathologic origins of neuropsychiatric disorders. Nevertheless, the exact pathophysiological mechanism for most cases remains unclear. Recent studies have demonstrated alterations in pathways of protein homeostasis (proteostasis) and identified several proteins that are misfolded and/or aggregated in the brains of patients with neuropsychiatric disorders, thus providing early evidence that disrupted proteostasis may be a contributing factor to their pathophysiology. Unlike neurodegenerative disorders in which massive neuronal and synaptic losses are observed, proteostasis impairments in neuropsychiatric disorders do not lead to robust neuronal death, but rather likely act via loss- and gain-of-function effects to disrupt neuronal and synaptic functions. Furthermore, abnormal activation of or overwhelmed endoplasmic reticulum and mitochondrial quality control pathways may exacerbate the pathophysiological changes initiated by impaired proteostasis, as these organelles are critical for proper neuronal functions and involved in the maintenance of proteostasis. This perspective article reviews recent findings implicating proteostasis impairments in the pathophysiology of neuropsychiatric disorders and explores how neuronal and synaptic functions may be impacted by disruptions in protein homeostasis. A greater understanding of the contributions by proteostasis impairment in neuropsychiatric disorders will help guide future studies to identify additional candidate proteins and new targets for therapeutic development.
    Keywords:  ER stress; mitochondria; neuropsychiatric disorders; protein aggregation; protein misfolding; proteostasis
    DOI:  https://doi.org/10.1016/j.biopsych.2021.09.001
  7. Cells. 2021 Nov 11. pii: 3121. [Epub ahead of print]10(11):
    With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage.
    Selin Altinok, Rebekah Sanchez-Hodge, Mariah Stewart, Kaitlan Smith, Jonathan C Schisler.
      Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintain protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensure cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, with a concentration on cardioprotection, neuroprotection, cancer, and autoimmune diseases. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.
    Keywords:  cancer; cardioprotection; co-chaperones; heat shock proteins; neuroprotection; protein degradation; protein folding; protein quality control
    DOI:  https://doi.org/10.3390/cells10113121
  8. Cell Chem Biol. 2021 Nov 22. pii: S2451-9456(21)00481-5. [Epub ahead of print]
    An allosteric inhibitor of bacterial Hsp70 chaperone potentiates antibiotics and mitigates resistance.
    Jordan Hosfelt, Aweon Richards, Meng Zheng, Carolina Adura, Brock Nelson, Amy Yang, Allison Fay, William Resager, Beatrix Ueberheide, J Fraser Glickman, Tania J Lupoli.
      DnaK is the bacterial homolog of Hsp70, an ATP-dependent chaperone that helps cofactor proteins to catalyze nascent protein folding and salvage misfolded proteins. In the pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), DnaK and its cofactors are proposed antimycobacterial targets, yet few small-molecule inhibitors or probes exist for these families of proteins. Here, we describe the repurposing of a drug called telaprevir that is able to allosterically inhibit the ATPase activity of DnaK and to prevent chaperone function by mimicking peptide substrates. In mycobacterial cells, telaprevir disrupts DnaK- and cofactor-mediated cellular proteostasis, resulting in enhanced efficacy of aminoglycoside antibiotics and reduced resistance to the frontline TB drug rifampin. Hence, this work contributes to a small but growing collection of protein chaperone inhibitors, and it demonstrates that these molecules disrupt bacterial mechanisms of survival in the presence of different antibiotic classes.
    Keywords:  DnaJ; DnaK; Hsp70; antibiotic adjuvants; chaperones; cofactors; mycobacteria; proteostasis; resistance; tuberculosis
    DOI:  https://doi.org/10.1016/j.chembiol.2021.11.004
  9. Cells. 2021 Oct 21. pii: 2835. [Epub ahead of print]10(11):
    The Cytotoxicity and Clearance of Mutant Huntingtin and Other Misfolded Proteins.
    Austin Folger, Yanchang Wang.
      Protein misfolding and aggregation are implicated in many neurodegenerative diseases. One of these diseases is Huntington's, which is caused by increased glutamine-encoding trinucleotide repeats within the Huntingtin gene. Like other misfolded proteins, mutated Huntingtin proteins with polyglutamine expansions are prone to aggregation. Misfolded proteins exist as soluble monomers, small aggregates, or as large insoluble inclusion bodies. Misfolded protein aggregates are believed to be cytotoxic by stressing the protein degradation machinery, disrupting membrane structure, or sequestering other proteins. We recently showed that expression of misfolded proteins lowers cellular free ubiquitin levels, which compromises the protein degradation machinery. Therefore, the efficient degradation of misfolded proteins is critical to preserve cell health. Cells employ two major mechanisms to degrade misfolded proteins. The first is the ubiquitin-proteasome system (UPS), which ubiquitinates and degrades misfolded proteins with the assistance of segregase Cdc48/p97. The UPS pathway is mainly responsible for the clearance of misfolded proteins present as monomers or smaller aggregates. The second pathway is macroautophagy/autophagy, in which protein aggregates or inclusion bodies are recruited into an autophagosome before transport to the vacuole/lysosome for degradation. This review is focused on the current understanding of the cytotoxicity of misfolded proteins as well as their clearance pathways, with a particular emphasis on mutant Huntingtin.
    Keywords:  Cdc48; autophagy; mutated Huntingtin; protein misfolding; ubiquitin-proteasome system (UPS)
    DOI:  https://doi.org/10.3390/cells10112835
  10. J Clin Neurosci. 2021 Nov 19. pii: S0967-5868(21)00550-6. [Epub ahead of print]
    The increase of α-synuclein and alterations of dynein in A53T transgenic and aging mouse.
    Yiqing Wang, Zhenjie Sun, Shouyun Du, Hongyu Wei, Xiuming Li, Xiaojing Li, Jiahui Shen, Xinya Chen, Zenglin Cai.
      The dynein protein plays a key role in the degradation pathway by attaching to targeted molecules and transporting the autophagosome to the centrosome. Aging plays an important role in the pathogenesis of Parkinson's disease (PD), but its effect on dynein is not clear. In this study we analyzed behavioral characteristics using the rod endurance test and climbing rod time test in different aged mice (3 months, 12 months, 20 months), and measured protein expression of dynein, α-synuclein, Tctex-1, and LC3 in the substantianigra of the mice by Western blot. The mRNA levels of dynein, α-synuclein, LC3 and Tctex-1 were measured by quantitative real time reverse transcription PCR, and detecting expression of dynein and α-synuclein by immunofluorescence. We found the motor functions of A53T mutant mice, in 12 months and 20 months, decreased more significantly compared with normal mice (p < 0.05). In addition, the expression of dynein, LC3-Ⅱ and Tctex-1 proteins in the substantia nigra of the two groups decreased with age. However, α-synuclein protein increased gradually with age, with significantly higher levels in the PD groups compared with age matched controls (p < 0.05). These results were confirmed by immunofluorescence. Our data demonstrates that dynein and other autophagy proteins change with age, and this is associated with increased α-synuclein. Therefore, therapeutics that prevent dynein dysfunction may offer novel treatments for PD and other autophagy related diseases.
    Keywords:  Aging; Autophagy; Dynein; Parkinson's disease (PD); α-Synuclein
    DOI:  https://doi.org/10.1016/j.jocn.2021.11.002
  11. Exp Mol Med. 2021 Nov 26.
    O-GlcNAcylation in health and neurodegenerative diseases.
    Byeong Eun Lee, Pann-Ghill Suh, Jae-Ick Kim.
      O-GlcNAcylation is a posttranslational modification that adds O-linked β-N-acetylglucosamine (O-GlcNAc) to serine or threonine residues of many proteins. This protein modification interacts with key cellular pathways involved in transcription, translation, and proteostasis. Although ubiquitous throughout the body, O-GlcNAc is particularly abundant in the brain, and various proteins commonly found at synapses are O-GlcNAcylated. Recent studies have demonstrated that the modulation of O-GlcNAc in the brain alters synaptic and neuronal functions. Furthermore, altered brain O-GlcNAcylation is associated with either the etiology or pathology of numerous neurodegenerative diseases, while the manipulation of O-GlcNAc exerts neuroprotective effects against these diseases. Although the detailed molecular mechanisms underlying the functional roles of O-GlcNAcylation in the brain remain unclear, O-GlcNAcylation is critical for regulating diverse neural functions, and its levels change during normal and pathological aging. In this review, we will highlight the functional importance of O-GlcNAcylation in the brain and neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s12276-021-00709-5
  12. iScience. 2021 Dec 17. 24(12): 103396
    Proteostasis regulated by testis-specific ribosomal protein RPL39L maintains mouse spermatogenesis.
    Qianxing Zou, Lele Yang, Ruona Shi, Yuling Qi, Xiaofei Zhang, Huayu Qi.
      Maintaining proteostasis is important for animal development. How proteostasis influences spermatogenesis that generates male gametes, spermatozoa, is not clear. We show that testis-specific paralog of ribosomal large subunit protein RPL39, RPL39L, is required for mouse spermatogenesis. Deletion of Rpl39l in mouse caused reduced proliferation of spermatogonial stem cells, malformed sperm mitochondria and flagella, leading to sub-fertility in males. Biochemical analyses revealed that lack of RPL39L deteriorated protein synthesis and protein quality control in spermatogenic cells, partly due to reduced biogenesis of ribosomal subunits and ribosome homeostasis. RPL39/RPL39L is likely assembled into ribosomes via H/ACA domain containing NOP10 complex early in ribosome biogenesis pathway. Furthermore, Rpl39l null mice exhibited compromised regenerative spermatogenesis after chemical insult and early degenerative spermatogenesis in aging mice. These data demonstrate that maintaining proteostasis is important for spermatogenesis, of which ribosome homeostasis maintained by ribosomal proteins coordinates translation machinery to the regulation of cellular growth.
    Keywords:  Developmental biology; Male reproductive endocrinology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2021.103396
  13. Biology (Basel). 2021 Nov 03. pii: 1127. [Epub ahead of print]10(11):
    Association between Sleep, Alzheimer's, and Parkinson's Disease.
    Sumire Matsumoto, Tomomi Tsunematsu.
      The majority of neurodegenerative diseases are pathologically associated with protein misfolding and aggregation. Alzheimer's disease (AD) is a type of dementia that slowly affects memory and cognitive function, and is characterized by the aggregation of the β-amyloid protein and tau neurofibrillary tangles in the brain. Parkinson's disease (PD) is a movement disorder typically resulting in rigidity and tremor, which is pathologically linked to the aggregation of α-synuclein, particularly in dopaminergic neurons in the midbrain. Sleep disorders commonly occur in AD and PD patients, and it can precede the onset of these diseases. For example, cognitively normal older individuals who have highly fragmented sleep had a 1.5-fold increased risk of subsequently developing AD. This suggests that sleep abnormalities may be a potential biomarker of these diseases. In this review, we describe the alterations of sleep in AD and PD, and discuss their potential in the early diagnosis of these diseases. We further discuss whether sleep disturbance could be a target for the treatment of these diseases.
    Keywords:  Alzheimer’s disease; EEG; Parkinson’s disease; REM behavior disorder; orexin; sleep; tau neurofibrillary tangles; α-synuclein; β-amyloid
    DOI:  https://doi.org/10.3390/biology10111127
  14. Biomedicines. 2021 Nov 09. pii: 1649. [Epub ahead of print]9(11):
    Structural and Computational Study of the GroEL-Prion Protein Complex.
    Aleksandra A Mamchur, Andrei V Moiseenko, Irina S Panina, Igor A Yaroshevich, Sofia S Kudryavtseva, Evgeny B Pichkur, Olga S Sokolova, Vladimir I Muronetz, Tatiana B Stanishneva-Konovalova.
      The molecular chaperone GroEL is designed to promote protein folding and prevent aggregation. However, the interaction between GroEL and the prion protein, PrPC, could lead to pathogenic transformation of the latter to the aggregation-prone PrPSc form. Here, the molecular basis of the interactions in the GroEL-PrP complex is studied with cryo-EM and molecular dynamics approaches. The obtained cryo-EM structure shows PrP to be bound to several subunits of GroEL at the level of their apical domains. According to MD simulations, the disordered N-domain of PrP forms much more intermolecular contacts with GroEL. Upon binding to the GroEL, the N-domain of PrP begins to form short helices, while the C-domain of PrP exhibits a tendency to unfold its α2-helix. In the absence of the nucleotides in the system, these processes are manifested at the hundred nanoseconds to microsecond timescale.
    Keywords:  Cryo-EM; GroEL; molecular chaperones; molecular dynamics; prion protein
    DOI:  https://doi.org/10.3390/biomedicines9111649
  15. Nature. 2021 Nov;599(7886): 706-708
    Artificial intelligence powers protein-folding predictions.
    Michael Eisenstein.
      
    Keywords:  Biological techniques; Computational biology and bioinformatics; Structural biology
    DOI:  https://doi.org/10.1038/d41586-021-03499-y
  16. Nat Commun. 2021 Nov 26. 12(1): 6778
    An atlas of protein turnover rates in mouse tissues.
    Zach Rolfs, Brian L Frey, Xudong Shi, Yoshitaka Kawai, Lloyd M Smith, Nathan V Welham.
      Protein turnover is critical to cellular physiology as well as to the growth and maintenance of tissues. The unique synthesis and degradation rates of each protein help to define tissue phenotype, and knowledge of tissue- and protein-specific half-lives is directly relevant to protein-related drug development as well as the administration of medical therapies. Using stable isotope labeling and mass spectrometry, we determine the in vivo turnover rates of thousands of proteins-including those of the extracellular matrix-in a set of biologically important mouse tissues. We additionally develop a data visualization platform, named ApplE Turnover, that enables facile searching for any protein of interest in a tissue of interest and then displays its half-life, confidence interval, and supporting measurements. This extensive dataset and the corresponding visualization software provide a reference to guide future studies of mammalian protein turnover in response to physiologic perturbation, disease, or therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41467-021-26842-3
  17. Life (Basel). 2021 Oct 22. pii: 1126. [Epub ahead of print]11(11):
    Examining the Toxicity of α-Synuclein in Neurodegenerative Disorders.
    Frank Y Shan, Kar-Ming Fung, Tarek Zieneldien, Janice Kim, Chuanhai Cao, Jason H Huang.
      α-synuclein is considered the main pathological protein in a variety of neurodegenerative disorders, such as Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. As of now, numerous studies have been aimed at examining the post-translational modifications of α-synuclein to determine their effects on α-synuclein aggregation, propagation, and oligomerization, as well as the potential cellular pathway dysfunctions caused by α-synuclein, to determine the role of the protein in disease progression. Furthermore, α-synuclein also appears to contribute to the fibrilization of tau and amyloid beta, which are crucial proteins in Alzheimer's disease, advocating for α-synuclein's preeminent role in neurodegeneration. Due to this, investigating the mechanisms of toxicity of α-synuclein in neurodegeneration may lead to a more proficient understanding of the timeline progression in neurodegenerative synucleinopathies and could thereby lead to the development of potent targeted therapies.
    Keywords:  Lewy body; Parkinson’s disease; dopamine; post-translational modifications; substantia nigra; synucleinopathy
    DOI:  https://doi.org/10.3390/life11111126
  18. Int J Mol Sci. 2021 Nov 20. pii: 12533. [Epub ahead of print]22(22):
    BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis.
    Marta Gómez-Almería, Sonia Burgaz, Carlos Costas-Insua, Carmen Rodríguez-Cueto, Irene Santos-García, Ignacio Rodríguez-Crespo, Concepción García, Manuel Guzmán, Eva de Lago, Javier Fernández-Ruiz.
      In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). To this end, we used mice bearing partial genetic deletion of the BiP gene (BiP+/- mice), which, for the ALS model, were crossed with mutant SOD1 (mSOD1) transgenic mice to generate mSOD1/BiP+/- double mutant mice. Our data revealed a more intense neurological decline in the double mutants, reflected in a greater deterioration of the neurological score and rotarod performance, with also a reduced animal survival, compared to mSOD1 transgenic mice. Such worsening was associated with higher microglial (labelled with Iba-1 immunostaining) and, to a lesser extent, astroglial (labelled with GFAP immunostaining) immunoreactivities found in the double mutants, but not with a higher loss of spinal motor neurons (labelled with Nissl staining) in the spinal cord. The morphological analysis of Iba-1 and GFAP-positive cells revealed a higher presence of activated cells, characterized by elevated cell body size and shorter processes, in double mutants compared to mSOD1 mice with normal BiP expression. In the case of the PD model, BiP+/- mice were unilaterally lesioned with the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). In this case, however, we did not detect a greater susceptibility to damage in mutant mice, as the motor defects caused by 6-OHDA in the pole test and the cylinder rearing test, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity (labelled with CD68 and GFAP immunostaining) detected in the substantia nigra were of similar magnitude in BiP+/- mice compared with wildtype animals. Therefore, our findings support the view that a dysregulation of the protein BiP may contribute to ALS pathogenesis. As BiP has been recently related to cannabinoid type-1 (CB1) receptor function, our work also opens the door to future studies on a possible link between BiP and the neuroprotective effects of cannabinoids that have been widely reported in this neuropathological context. In support of this possibility, preliminary data indicate that CB1 receptor levels are significantly reduced in mSOD1 mice having partial deletion of BiP gene.
    Keywords:  BiP interactor protein; BiP+/− mice; CB1 receptors; Parkinson’s disease; amyotrophic lateral sclerosis; cannabinoids; mSOD1 mice; spinal cord
    DOI:  https://doi.org/10.3390/ijms222212533
  19. Behav Brain Res. 2021 Nov 22. pii: S0166-4328(21)00568-4. [Epub ahead of print] 113680
    Prion protein complexed to a DNA aptamer induce behavioral and synapse dysfunction in mice.
    Mariana P B Gomes, Emanuelle V de Lima, Fernanda G Q Barros-Aragão, Yulli M Passos, Felipe S Lemos, Daniele C Zamberlan, Gabriel Ribeiro, Bruno Macedo, Natalia C Ferreira, Jerson L Silva, Claudia P Figueiredo, Julia R Clarke, Yraima Cordeiro.
      Conversion of the cellular prion protein (PrPC) into the scrapie form (PrPSc) is the leading step to the development of transmissible spongiform encephalopathies (TSEs), still incurable neurodegenerative disorders. Interaction of PrPC with cellular and synthetic ligands that induce formation of scrapie-like conformations has been deeply investigated in vitro. Different nucleic acid (NA) sequences bind PrP and convert it to β-sheet-rich or unfolded species; among such NAs, a 21-mer double-stranded DNA, D67, was shown to induce formation of PrP aggregates that were cytotoxic. However, in vivo effects of these PrP-DNA complexes were not explored. Herein, aggregates of recombinant full-length PrP (rPrP23-231) induced by interaction with the D67 aptamer were inoculated into the lateral ventricle of Swiss mice and acute effects were investigated. The aggregates had no influence on emotional, locomotor and motor behavior of mice. In contrast, mice developed cognitive impairment and hippocampal synapse loss, which was accompanied by intense activation of glial cells in this brain region. Our results suggest that the i.c.v. injection of rPrP:D67 aggregates is an interesting model to study the neurotoxicity of aggregated PrP in vivo, and that glial cell activation may be an important step for behavioral and cognitive dysfunction in prion diseases.
    Keywords:  Behavior; Memory; Neurotoxicity; Nucleic acid; Prion protein; Protein aggregation; Protein-DNA interaction; Scrapie; Synapse
    DOI:  https://doi.org/10.1016/j.bbr.2021.113680
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