scholarly journals Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation

2019 ◽  
Author(s):  
John J. Chen ◽  
Diane L. Nathaniel ◽  
Preethi Raghavan ◽  
Maxine Nelson ◽  
Ruilin Tian ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Frontotemporal Dementia ◽  
Human Cell ◽  
Membrane Repair ◽  
Critical Step ◽  
Crispr Interference ◽  
Escrt Machinery ◽  
Systematic Understanding ◽  
Tau Aggregation

ABSTRACTIntercellular propagation of protein aggregation is emerging as a key mechanism in the progression of several neurodegenerative diseases, including Alzheimer’s Disease and frontotemporal dementia. However, we lack a systematic understanding of the cellular path-ways controlling prion-like propagation. To uncover such pathways, we performed CRISPR interference (CRISPRi) screens in a human cell-based model of propagation of tau aggregation. Our screens uncovered that knockdown of several components of the ESCRT machinery, including CHMP6, or CHMP2A in combination with CHMP2B (a gene linked to familial fronto-temporal dementia), promote propagation of tau aggregation. We found that knockdown of these genes caused damage to endolysosomal membranes, consistent with a role for the ESCRT pathway in endolysosomal membrane repair. Leakiness of the endolysosomal compartment significantly enhanced prion-like propagation of tau aggregation, likely by making tau seeds more available to pools of cytoplasmic tau. Together, these findings suggest that endolysosomal escape is a critical step in tau propagation.

scholarly journals PIKfyve inhibition blocks endolysosomal escape of α-synuclein fibrils and spread of α-synuclein aggregation

2021 ◽  
Author(s):  
Stephanie K. See ◽  
Merissa Chen ◽  
Sophie Bax ◽  
Ruilin Tian ◽  
Amanda Woerman ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Neurodegenerative Diseases ◽  
Human Cell ◽  
Therapeutic Target ◽  
Therapeutic Strategies ◽  
Early Endosome ◽  
Potential Therapeutic Target ◽  
Critical Step ◽  
Genome Wide ◽  
A Genome

ABSTRACTThe inter-cellular prion-like propagation of α-synuclein aggregation is emerging as an important mechanism driving the progression of neurodegenerative diseases including Parkinson’s disease and multiple system atrophy (MSA). To discover therapeutic strategies reducing the spread of α-synuclein aggregation, we performed a genome-wide CRISPR interference screen in a human cell-based model. We discovered that inhibiting PIKfyve dramatically reduced α-synuclein aggregation induced with both recombinant α-synuclein fibrils and fibrils isolated from MSA patient brain. While PIKfyve inhibition did not affect fibril uptake or α-synuclein clearance or secretion, it reduced α-synuclein trafficking from the early endosome to the lysosome, thereby limiting fibril escape from the lysosome and reducing the amount of fibrils that reach cytosolic α-synuclein to induce aggregation. These findings point to the endolysosomal transport of fibrils as a critical step in the propagation of α-synuclein aggregation and a potential therapeutic target.

scholarly journals Observation of liquid-liquid phase separation of ataxin-3 and quantitative evaluation of its concentration in a single droplet using Raman microscopy

2021 ◽  
Author(s):  
Kazuki Murakami ◽  
Shinji Kajimoto ◽  
Daiki Shibata ◽  
Kunisato Kuroi ◽  
Fumihiko Fujii ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Quantitative Evaluation ◽  
Raman Microscopy ◽  
Liquid Phase Separation ◽  
Biological Processes ◽  
Single Droplet ◽  
Liquid Liquid Phase Separation

Liquid–liquid phase separation (LLPS) plays an important role in a variety of biological processes and is also associated with protein aggregation in neurodegenerative diseases. Quantification of LLPS is necessary to...

The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors

2021 ◽  
Author(s):  
Benjamin C Creekmore ◽  
Yi-Wei Chang ◽  
Edward B Lee
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Electron Tomography ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
X Ray Crystallography ◽  
New Information ◽  
A Cell ◽  
Regulate Protein

Abstract Neurodegenerative diseases are characterized by the accumulation of misfolded proteins. This protein aggregation suggests that abnormal proteostasis contributes to aging-related neurodegeneration. A better fundamental understanding of proteins that regulate proteostasis may provide insight into the pathophysiology of neurodegenerative disease and may perhaps reveal novel therapeutic opportunities. The 26S proteasome is the key effector of the ubiquitin-proteasome system responsible for degrading polyubiquitinated proteins. However, additional factors, such as valosin-containing protein (VCP/p97/Cdc48) and C9orf72, play a role in regulation and trafficking of substrates through the normal proteostasis systems of a cell. Nonhuman AAA+ ATPases, such as the disaggregase Hsp104, also provide insights into the biochemical processes that regulate protein aggregation. X-ray crystallography and cryo-electron microscopy (cryo-EM) structures not bound to substrate have provided meaningful information about the 26S proteasome, VCP, and Hsp104. However, recent cryo-EM structures bound to substrate have provided new information about the function and mechanism of these proteostasis factors. Cryo-EM and cryo-electron tomography data combined with biochemical data have also increased the understanding of C9orf72 and its role in maintaining proteostasis. These structural insights provide a foundation for understanding proteostasis mechanisms with near-atomic resolution upon which insights can be gleaned regarding the pathophysiology of neurodegenerative diseases.

scholarly journals The Missing Heritability of Sporadic Frontotemporal Dementia: New Insights from Rare Variants in Neurodegenerative Candidate Genes

2019 ◽  
Vol 20 (16) ◽  
pp. 3903 ◽  
Author(s):  
Miriam Ciani ◽  
Cristian Bonvicini ◽  
Catia Scassellati ◽  
Matteo Carrara ◽  
Carlo Maj ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Frontotemporal Dementia ◽  
Candidate Genes ◽  
Early Onset ◽  
Genetic Factors ◽  
Rare Variants ◽  
Late Onset ◽  
Genetic Effect ◽  
Lewy Body Dementia ◽  
Missing Heritability

Frontotemporal dementia (FTD) is a common form of dementia among early-onset cases. Several genetic factors for FTD have been revealed, but a large proportion of FTD cases still have an unidentified genetic origin. Recent studies highlighted common pathobiological mechanisms among neurodegenerative diseases. In the present study, we investigated a panel of candidate genes, previously described to be associated with FTD and/or other neurodegenerative diseases by targeted next generation sequencing (NGS). We focused our study on sporadic FTD (sFTD), devoid of disease-causing mutations in GRN, MAPT and C9orf72. Since genetic factors have a substantially higher pathogenetic contribution in early onset patients than in late onset dementia, we selected patients with early onset (<65 years). Our study revealed that, in 50% of patients, rare missense potentially pathogenetic variants in genes previously associated with Alzheimer’s disease, Parkinson disease, amyotrophic lateral sclerosis and Lewy body dementia (GBA, ABCA7, PARK7, FUS, SORL1, LRRK2, ALS2), confirming genetic pleiotropy in neurodegeneration. In parallel, a synergic genetic effect on FTD is suggested by the presence of variants in five different genes in one single patient. Further studies employing genome-wide approaches might highlight pathogenic variants in novel genes that explain the still missing heritability of FTD.

scholarly journals Red Ginseng Inhibits Tau Aggregation and Promotes Tau Dissociation In Vitro

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Soo Jung Shin ◽  
Yong Ho Park ◽  
Seong Gak Jeon ◽  
Sujin Kim ◽  
Yunkwon Nam ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Paired Helical Filaments ◽  
Red Ginseng ◽  
Tau Pathology ◽  
Korean Red Ginseng ◽  
Ginseng Extract ◽  
Microtubule Binding Domain ◽  
Mature Neurons ◽  
Tau Aggregation

Tau, a microtubule-associated protein expressed in mature neurons, interacts with tubulin to promote the assembly and stabilization of microtubules. However, abnormally hyperphosphorylated tau dissociates from microtubules and self-aggregates. Tau aggregates, including paired helical filaments and neurofibrillary tangles, promote neuronal dysfunction and death and are the defining neuropathological feature of tauopathies. Therefore, suppressing tau aggregation or stimulating the dissociation of tau aggregates has been proposed as an effective strategy for treating neurodegenerative diseases associated with tau pathology such as Alzheimer’s disease (AD) and frontotemporal dementia. Interestingly, ginsenosides extracted from Panax ginseng reduced the hippocampal and cortical expression of phosphorylated tau in a rat model of AD. However, no studies have been conducted into the effect of red ginseng (RG) and its components on tau pathology. Here, we evaluated the effect of Korean red ginseng extract (KRGE) and its components on the aggregation and disassociation of tau. Using the thioflavin T assay, we monitored the change in fluorescence produced by the aggregation or disassociation of tau K18, an aggregation-prone fragment of tau441 containing the microtubule-binding domain. Our analysis revealed that KRGE not only inhibited tau aggregation but also promoted the dissociation of tau aggregates. In addition, the KRGE fractions, such as saponin, nonsaponin, and nonsaponin fraction with rich polysaccharide, also inhibited tau aggregation and promoted the dissociation of tau aggregates. Our observations suggest that RG could be a potential therapeutic agent for the treatment of neurodegenerative diseases associated with tauopathy.

scholarly journals Supersaturation is a major driving force for protein aggregation in neurodegenerative diseases

2015 ◽  
Vol 36 (2) ◽  
pp. 72-77 ◽  
Author(s):  
Prajwal Ciryam ◽  
Rishika Kundra ◽  
Richard I. Morimoto ◽  
Christopher M. Dobson ◽  
Michele Vendruscolo
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Driving Force

Biochemical and immunological aspects of protein aggregation in neurodegenerative diseases

2014 ◽  
Vol 11 (6) ◽  
pp. 1503-1512 ◽  
Author(s):  
Fatemeh Shojaei ◽  
Naemeh Tavakolinia ◽  
Adeleh Divsalar ◽  
Thomas Haertlé ◽  
Ali Akbar Saboury ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation
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