scholarly journals Prion-like C-terminal domain of TDP-43 and α-Synuclein interact synergistically to generate neurotoxic hybrid fibrils

2020 ◽  
Author(s):  
Shailendra Dhakal ◽  
Courtney E Wyant ◽  
Hannah E George ◽  
Sarah E Morgan ◽  
Vijayaraghavan Rangachari
Keyword(s):  
Lewy Bodies ◽  
Amyloid Formation ◽  
Liquid Droplets ◽  
Cellular Functions ◽  
Parkinsons Disease ◽  
Terminal Domain ◽  
Amyloid Aggregates ◽  
The Individual ◽  
Lateral Sclerosis ◽  
Selective Interactions

Aberrant aggregation and amyloid formation of tar DNA binding protein (TDP-43) and αsynuclein (αS) underlie frontotemporal dementia (FTD) and Parkinsons disease (PD), respectively. Amyloid inclusions of TDP-43 and αS are also commonly co-observed in amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB) and Alzheimer disease (AD). Emerging evidence from cellular and animal models show colocalization of the TDP-43 and αS aggregates, raising the possibility of direct interactions and coaggregation between the two proteins. In this report, we set out to answer this question by investigating the interactions between αS and prion-like pathogenic C-terminal domain of TDP-43 (TDP-43 PrLD). PrLD is an aggregation-prone fragment generated both by alternative splicing as well as aberrant proteolytic cleavage of full length TDP-43. Our results indicate that two proteins interact in a synergistic manner to augment each others aggregation towards hybrid fibrils. While monomers, oligomers and sonicated fibrils of αS seed TDP-43 PrLD monomer aggregation, TDP-43 PrLD fibrils failed to seed αS monomers indicating selective interactions. Furthermore, αS modulates liquid droplets formed by TDP-43 PrLD and RNA to promote insoluble amyloid aggregates. Importantly, the cross-seeded hybrid aggregates show greater cytotoxicity as compared to the individual homotypic aggregates suggesting that the interactions between the two proteins have a discernable impact on cellular functions. Together, these results bring forth insights into TDP-43 PrLD - αS interactions that could help explain clinical and pathological presentations in patients with co-morbidities involving the two proteins.

scholarly journals Systematic Review and Meta-Analysis Protocol: Beta adrenoreceptor drugs and risk of Parkinsons disease

2021 ◽  
Author(s):  
Ambrish Singh ◽  
Salman Hussain ◽  
Sreelatha Akkala ◽  
Jitka Klugarova ◽  
Andrea Pokorna ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Meta Analysis ◽  
Lewy Bodies ◽  
Epidemiological Studies ◽  
Beta Agonist ◽  
Parkinsons Disease ◽  
Beta Adrenoceptors ◽  
Critical Appraisal Tool ◽  
The Individual ◽  
System Disorder

Parkinsons disease (PD) is a progressive nervous system disorder characterised by the loss of dopaminergic neurons leading to motor and non-motor symptoms. Accumulation of α-synuclein protein (SNCA) in the form of Lewy bodies has been observed in dopaminergic neurons of PD patients. Potential relationships between β-adrenergic drugs (agonists and antagonist) and SNCA synthesis in PD have been recently suggested. This study aims to systematically review the evidence from various epidemiological studies that analysed the association between beta-adrenoceptors (agonists and antagonists) and the risk of PD. Biomedical databases such as PubMed and Embase will be searched to identify the individual studies that reported the relationship between beta-adrenoceptors and the risk of PD. JBI critical appraisal tool scale will be used to assess the quality of included studies. The primary outcome will be to compute the pooled risk of PD among beta-agonist and antagonist users. Furthermore, we will consider the pooled risk of PD based on study design, types of beta-agonist or antagonist exposure under secondary outcomes. RevMan 5, STATA 16, and ProMeta 3.0 will be used to conduct the statistical analysis.

scholarly journals An integrative structural model of the full-length gp16 ATPase in bacteriophage phi29 DNA packaging motor

2020 ◽  
Author(s):  
Abdullah F.U.H. Saeed ◽  
Chun Chan ◽  
Hongxin Guan ◽  
Bing Gong ◽  
Peixuan Guo ◽  
...  
Keyword(s):  
Structural Model ◽  
Md Simulations ◽  
Full Length ◽  
Nucleic Acid Binding ◽  
Multiple Sources ◽  
Cellular Functions ◽  
Motor Complex ◽  
Terminal Domain ◽  
Binding Surface ◽  
The Individual

ABSTRACTBiological motors, ubiquitous in living systems, convert chemical energy into different kinds of mechanical motions critical to cellular functions. Most of these biomotors belong to a group of enzymes known as ATPases, which adopt a multi-subunit ring-shaped structure and hydrolyze adenosine triphosphate (ATP) to generate forces. The gene product 16 (gp16), an ATPase in bacteriophage □29, is among the most powerful biomotors known. It can overcome substantial resisting forces from entropic, electrostatic, and DNA bending sources to package double-stranded DNA (dsDNA) into a preformed protein shell (procapsid). Despite numerous studies of the □29 packaging mechanism, a structure of the full-length gp16 is still lacking, let alone that of the packaging motor complex that includes two additional molecular components: a connector gp10 protein and a prohead RNA (pRNA). Here we report the crystal structure of the C-terminal domain of gp16 (gp16-CTD). Structure-based alignment of gp16-CTD with related RNase H-like nuclease domains revealed a nucleic acid binding surface in gp16-CTD, whereas no nuclease activity has been detected for gp16. Subsequent molecular dynamics (MD) simulations showed that this nucleic acid binding surface is likely essential for pRNA binding. Furthermore, our simulations of a full-length gp16 structural model highlighted a dynamic interplay between the N-terminal domain (NTD) and CTD of gp16, which may play a role in driving DNA movement into the procapsid, providing structural support to the previously proposed inchworm model. Lastly, we assembled an atomic structural model of the complete □29 dsDNA packaging motor complex by integrating structural and experimental data from multiple sources. Collectively, our findings provided a refined inchworm-revolution model for dsDNA translocation in bacteriophage □29 and suggested how the individual domains of gp16 work together to power such translocation.ABSTRACT (SHORT)Biological motors, ubiquitous in living systems, convert chemical energy into different kinds of mechanical motions critical to cellular functions. The gene product 16 (gp16) in bacteriophage □29 is among the most powerful biomotors known, which adopts a multi-subunit ring-shaped structure and hydrolyzes ATP to package double-stranded DNA (dsDNA) into a preformed procapsid. Here we report the crystal structure of the C-terminal domain of gp16 (gp16-CTD). Structure-based alignment and molecular dynamics (MD) simulations revealed an essential binding surface of gp16-CTD for prohead RNA (pRNA), a unique component of the motor complex. Furthermore, our simulations highlighted a dynamic interplay between the N-terminal domain (NTD) and CTD of gp16, which may play a role in driving DNA movement into the procapsid. Lastly, we assembled an atomic structural model of the complete □29 dsDNA packaging motor complex by integrating structural and experimental data from multiple sources. Collectively, our findings provided a refined inchworm-revolution model for dsDNA translocation in bacteriophage □29 and suggested how the individual domains of gp16 work together to power such translocation.

scholarly journals The individual course of neuropsychiatric symptoms in people with Alzheimer's and Lewy body dementia: 12-year longitudinal cohort study

2019 ◽  
Vol 216 (1) ◽  
pp. 43-48 ◽  
Author(s):  
Audun Osland Vik-Mo ◽  
Lasse Melvaer Giil ◽  
Miguel Germán Borda ◽  
Clive Ballard ◽  
Dag Aarsland
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuropsychiatric Symptoms ◽  
Personalised Medicine ◽  
Lewy Bodies ◽  
Lewy Body Dementia ◽  
Psychotic Symptoms ◽  
Primary Inclusion ◽  
The Individual

IntroductionUnderstanding the natural course of neuropsychiatric symptoms (NPS) in dementia is important for planning patient care and trial design, but few studies have described the long-term course of NPS in individuals.MethodPrimary inclusion of 223 patients with suspected mild dementia from general practice were followed by annual assessment, including the Neuropsychiatric Inventory (NPI), for up to 12 years. Total and item NPI scores were classified as stable, relapsing, single episodic or not present based on 4.96 (s.d. 2.3) observations (98% completeness of longitudinal data) for 113 patients with Alzheimer's disease and 84 patients with LBD (68 dementia with Lewy bodies and 16 Parkinson's disease dementia).ResultsWe found that 80% had stable NPI total ≥1, 50% had stable modest NPI total ≥12 and 25% had stable NPI total ≥24 scores. Very severe NPS (≥48) were mostly single episodes, but 8% of patients with Alzheimer's disease had stable severe NPS. Patients with Alzheimer's disease and the highest 20% NPI total scores had a more stable or relapsing course of four key symptoms: aberrant motor behaviour, aggression/agitation, delusions and irritability (odds ratio 55, P < 0.001). This was not seen in LBD. Finally, 57% of patients with Alzheimer's disease and 84% of patients with LBD had reoccurring psychotic symptoms.ConclusionsWe observed a highly individual course of NPS, with most presenting as a single episode or relapsing; a stable course was less common, especially in LBD. These findings demonstrate the importance of an individualised approach (i.e. personalised medicine) in dementia care.

scholarly journals The Effect of Octapeptide Repeats on Prion Folding and Misfolding

2021 ◽  
Vol 22 (4) ◽  
pp. 1800
Author(s):  
Kun-Hua Yu ◽  
Mei-Yu Huang ◽  
Yi-Ru Lee ◽  
Yu-Kie Lin ◽  
Hau-Ren Chen ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Age Of Onset ◽  
Prion Diseases ◽  
Critical Role ◽  
Threshold Effect ◽  
Central Feature ◽  
Terminal Domain ◽  
Amyloid Aggregates

Misfolding of prion protein (PrP) into amyloid aggregates is the central feature of prion diseases. PrP has an amyloidogenic C-terminal domain with three α-helices and a flexible tail in the N-terminal domain in which multiple octapeptide repeats are present in most mammals. The role of the octapeptides in prion diseases has previously been underestimated because the octapeptides are not located in the amyloidogenic domain. Correlation between the number of octapeptide repeats and age of onset suggests the critical role of octapeptide repeats in prion diseases. In this study, we have investigated four PrP variants without any octapeptides and with 1, 5 and 8 octapeptide repeats. From the comparison of the protein structure and the thermal stability of these proteins, as well as the characterization of amyloids converted from these PrP variants, we found that octapeptide repeats affect both folding and misfolding of PrP creating amyloid fibrils with distinct structures. Deletion of octapeptides forms fewer twisted fibrils and weakens the cytotoxicity. Insertion of octapeptides enhances the formation of typical silk-like fibrils but it does not increase the cytotoxicity. There might be some threshold effect and increasing the number of peptides beyond a certain limit has no further effect on the cell viability, though the reasons are unclear at this stage. Overall, the results of this study elucidate the molecular mechanism of octapeptides at the onset of prion diseases.

User Centered Approach to the Supra-Functional Needs of People Living with Amyotrophic Lateral Sclerosis (ALS)

2020 ◽  
Author(s):  
Deana McDonagh ◽  
Kayla Arquines ◽  
Elizabeth T. Hsiao-Wecksler ◽  
Mahshid Mansouri ◽  
Girish Krishnan ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Design Thinking ◽  
Healthcare Management ◽  
User Centered Design ◽  
Emotional Needs ◽  
Empathic Understanding ◽  
The Individual ◽  
Lateral Sclerosis ◽  
User Centered

Abstract User-centered design relies upon the appreciation that assistive technology device solutions need to include the functional and supra-functional (e.g., emotional, social, cultural) needs of users. Developing solutions without basing decision-making on both quantitative (functional) and qualitative (supra-functional) needs can lead to imbalanced devices, services, and/or environments. Satisfying both functional and supra-functional needs is the foundation of user-centered design, which in itself relies upon empathic understanding of the person that one is aiming to serve. This paper presents a study of the lived experiences of people living with Amyotrophic Lateral Sclerosis, their caregivers, and members of the healthcare management team from a human-centered perspective in the pursuit of pain points, deeper understanding of the emotional needs, and revelation of opportunities for improving quality of life and human experience through more user-centered design. We focus on user-centered design-thinking research tools (e.g., mood boards, journey maps, personas) to (a) understand the authentic experience of the individual in their vernacular and their terminology, and (b) to support a data rich conversation that focuses upon both functional and supra-functional needs to highlight opportunities for design interventions).

Shy-Drager Syndrome. Neuropathological Correlation and Response to Levodopa Therapy

1976 ◽  
Vol 3 (3) ◽  
pp. 167-173 ◽  
Author(s):  
Jacques De Lean ◽  
John H.N. Deck
Keyword(s):  
Lewy Bodies ◽  
Sympathetic Ganglia ◽  
Levodopa Therapy ◽  
Striatonigral Degeneration ◽  
Preganglionic Neurons ◽  
Progressive Loss ◽  
System Degeneration ◽  
Nigral Degeneration ◽  
Depressor Action ◽  
Lateral Sclerosis

SUMMARY:The post-mortem examination of the nervous system of a patient with Shy-Drager syndrome successfully treated with levodopa (Sharpe et al, 1972) revealed features of striato-nigral degeneration and amyotrophic lateral sclerosis, a cerebellar system degeneration and a loss of approximately 75% of sympathetic preganglionic neurons. Lewy bodies were not present and no detectable changes were observed in the sympathetic prevertebral ganglia.While the limited and transient beneficial effect of levodopa on the bradykinesia in our case is possibly due to the progressive loss of striatal dopaminergic receptors seen in striatonigral degeneration, we propose that in Shy-Drager syndrome, levodopa therapy benefits orthostatic hypotension because of a suppression of the central depressor action of this drug. This suppression is attributable to functional disconnection of sympathetic ganglia secondary to the loss of preganglionic neurons or to degeneration of central autonomic catechoiaminergic systems.

scholarly journals Different motilities of microtubules driven by kinesin-1 and kinesin-14 motors patterned on nanopillars

2020 ◽  
Vol 6 (4) ◽  
pp. eaax7413 ◽  
Author(s):  
Taikopaul Kaneko ◽  
Ken’ya Furuta ◽  
Kazuhiro Oiwa ◽  
Hirofumi Shintaku ◽  
Hidetoshi Kotera ◽  
...  
Keyword(s):  
Motor Protein ◽  
Cellular Functions ◽  
Collective Dynamics ◽  
Individual Effects ◽  
The Individual ◽  
Experimental Difficulty

Kinesin is a motor protein that plays important roles in a variety of cellular functions. In vivo, multiple kinesin molecules are bound to cargo and work as a team to produce larger forces or higher speeds than a single kinesin. However, the coordination of kinesins remains poorly understood because of the experimental difficulty in controlling the number and arrangement of kinesins, which are considered to affect their coordination. Here, we report that both the number and spacing significantly influence the velocity of microtubules driven by nonprocessive kinesin-14 (Ncd), whereas neither the number nor the spacing changes the velocity in the case of highly processive kinesin-1. This result was realized by the optimum nanopatterning method of kinesins that enables immobilization of a single kinesin on a nanopillar. Our proposed method enables us to study the individual effects of the number and spacing of motors on the collective dynamics of multiple motors.

scholarly journals Structural basis of outer dynein arm intraflagellar transport by the transport adaptor protein ODA16 and the intraflagellar transport protein IFT46

2017 ◽  
Vol 292 (18) ◽  
pp. 7462-7473 ◽  
Author(s):  
Michael Taschner ◽  
André Mourão ◽  
Mayanka Awasthi ◽  
Jerome Basquin ◽  
Esben Lorentzen
Keyword(s):  
Protein Complexes ◽  
Adaptor Protein ◽  
Intraflagellar Transport ◽  
Structural Basis ◽  
Fallopian Tubes ◽  
Large Protein ◽  
Terminal Domain ◽  
Unicellular Organisms ◽  
Motile Cilia ◽  
The Individual

Motile cilia are found on unicellular organisms such as the green alga Chlamydomonas reinhardtii, on sperm cells, and on cells that line the trachea and fallopian tubes in mammals. The motility of cilia relies on a number of large protein complexes including the force-generating outer dynein arms (ODAs). The transport of ODAs into cilia has been previously shown to require the transport adaptor ODA16, as well as the intraflagellar transport (IFT) protein IFT46, but the molecular mechanism by which ODAs are recognized and transported into motile cilia is still unclear. Here, we determined the high-resolution crystal structure of C. reinhardtii ODA16 (CrODA16) and mapped the binding to IFT46 and ODAs. The CrODA16 structure revealed a small 80-residue N-terminal domain and a C-terminal 8-bladed β-propeller domain that are both required for the association with the N-terminal 147 residues of IFT46. The dissociation constant of the IFT46-ODA16 complex was 200 nm, demonstrating that CrODA16 associates with the IFT complex with an affinity comparable with that of the individual IFT subunits. Furthermore, we show, using ODAs extracted from the axonemes of C. reinhardtii, that the C-terminal β-propeller but not the N-terminal domain of CrODA16 is required for the interaction with ODAs. These data allowed us to present an architectural model for ODA16-mediated IFT of ODAs.

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