Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice

The Journal of Experimental Medicine, Journal Year: 2016, Volume and Issue: 213(12), P. 2635 - 2654

Published: Oct. 17, 2016

Filamentous tau aggregates are hallmark lesions in numerous neurodegenerative diseases, including Alzheimer’s disease (AD). Cell culture and animal studies showed that fibrils can undergo cell-to-cell transmission seed aggregation of soluble tau, but this phenomenon was only robustly demonstrated models overexpressing tau. In study, we found intracerebral inoculation purified from AD brains (AD-tau), not synthetic fibrils, resulted the formation abundant inclusions anatomically connected brain regions nontransgenic mice. Recombinant human seeded by AD-tau revealed unique conformational features distinct which could underlie differential potency seeding physiological levels to aggregate. Therefore, our study establishes a mouse model sporadic tauopathies points important differences between generated artificially authentic ones develop brains.

Language: Английский

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Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease

The Journal of Experimental Medicine, Journal Year: 2016, Volume and Issue: 213(9), P. 1759 - 1778

Published: Aug. 8, 2016

Parkinson's disease (PD) is characterized by the progressive appearance of intraneuronal Lewy aggregates, which are primarily composed misfolded α-synuclein (α-syn). The aggregates believed to propagate via neural pathways following a stereotypical pattern, starting in olfactory bulb (OB) and gut. We hypothesized that injection fibrillar α-syn into OB wild-type mice would recreate sequential progression Lewy-like pathology, while triggering deficits. demonstrate injected fibrils recruit endogenous pathological spread transneuronally over several months, initially network later distant brain regions. seeded inclusions contain posttranslationally modified Thioflavin S positive, indicative amyloid fibrils. spreading pathology induces specific Thus, we propagating triggered functionally detrimental. Collectively, have created mouse model prodromal PD.

Language: Английский

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Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations

Movement Disorders, Journal Year: 2018, Volume and Issue: 33(5), P. 660 - 677

Published: April 11, 2018

ABSTRACT The greatest unmet therapeutic need in Parkinson's disease is the development of treatment that slows relentless progression neurodegenerative process. concept “disease modification” encompasses intervention types ranging from those designed to slow underlying degeneration treatments directed at regenerating or replacing lost neurons. To date all attempts develop effective disease‐modifying therapy have failed. Many reasons been proposed for these failures including our rudimentary understanding pathogenesis and assumption each targeted mechanisms apply most patients with same clinical diagnosis. Here we review aspects this broad field general concepts past challenges followed by a discussion approaches under following 4 categories: (1) α‐synuclein, (2) pathogenic distinct α‐synuclein (most also potentially triggered toxicity), (3) non‐ SNCA genetic subtypes “PD,” (4) possible interventions not directly influencing PD pathobiology. We emphasize are currently active highlight wide range important outstanding questions concerns will be considered advance modification PD. Critically, it unknown whether dysfunctional molecular pathways/organelles amenable occur sequential fashion across clinically affected individuals manifest differentially independent It there no “order disruption” applicable but, rather, “type dependent on factors, variability other causes heterogeneity Knowing when (early vs late), which (eg, synaptic transmission, endosomal sorting maturation, lysosomal degradation, mitochondrial biogenesis), whom (PD subtype) specific disrupted cell pathways truly versus compensatory even protective, considering use single combined (“cocktails”) putative therapies selectively target processes. Beyond current phase 2 3 studies underway evaluating oxidative stress (inosine), cytosolic Ca 2+ (isradipine), iron (deferiprone), extracellular (passive immunization), upcoming trials affecting c‐Abl, glucagon‐like peptide‐1, glucocerebrosidase, might argued further populations enriched process doomed repeat past. © 2018 International Parkinson Movement Disorder Society

Language: Английский

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Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

Frontiers in Pharmacology, Journal Year: 2020, Volume and Issue: 11

Published: April 23, 2020

Alpha-synuclein (α-Syn) is a key protein involved in Parkinson's disease (PD) pathology. PD characterized by the loss of dopaminergic neuronal cells substantia nigra pars compacta and abnormal accumulation aggregation α-Syn form Lewy bodies neurites. More precisely, associated with dysfunctionality degeneration neurons PD. Moreover, mutations SNCA gene, which encodes α-Syn, cause familial forms are basis sporadic risk. Given role pathology PD, animal models that reflect widespread progressive formation aggregates different areas brain constitute valuable tool. Indeed, important for understanding molecular mechanisms might contribute to development validation new therapies. In absence faithfully reproduce human recent years, numerous based on have been generated. this review, we summarize main features pre-formed fibrils (PFFs) model recombinant adeno-associated virus vector (rAAV) mediated overexpression models, providing detailed comparative analysis both models. Here, discuss how each has contributed our advantages weakness them.Here, show injection PFFs rAAV lead pattern rodents. First, trigger body-like inclusions regions directly interconnected site, suggesting there an inter-neuronal transmission contrast, rAAV-mediated limits within transduced neurons. Second, phosphorylated obtained predominantly nuclear punctate appearance becomes diffuse along fibers, whereas cytoplasmic reminiscent

Language: Английский

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Like prions: the propagation of aggregated tau and α-synuclein in neurodegeneration

Brain, Journal Year: 2016, Volume and Issue: 140(2), P. 266 - 278

Published: Sept. 21, 2016

The abnormal aggregation of a small number known proteins underlies the most common human neurodegenerative diseases. In tauopathies and synucleinopathies, normally soluble intracellular tau α-synuclein become insoluble filamentous. recent years, non-cell autonomous mechanisms aggregate formation have come to fore, suggesting that nucleation-dependent may occur in localized fashion followed by seed-dependent propagation. There is long prodromal phase between protein aggregates appearance first clinical symptoms, which manifest only after extensive propagation, opening novel therapeutic avenues.

Language: Английский

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Emerging therapies in Parkinson disease — repurposed drugs and new approaches

Nature Reviews Neurology, Journal Year: 2019, Volume and Issue: 15(4), P. 204 - 223

Published: March 12, 2019

Language: Английский

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Progress towards therapies for disease modification in Parkinson's disease

The Lancet Neurology, Journal Year: 2021, Volume and Issue: 20(7), P. 559 - 572

Published: June 16, 2021

Language: Английский

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Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer's disease and Parkinson's disease

Drug Design Development and Therapy, Journal Year: 2017, Volume and Issue: Volume11, P. 797 - 810

Published: March 1, 2017

Abstract: Alzheimer’s disease and Parkinson’s are two common neurodegenerative diseases of the elderly people that have devastating effects in terms morbidity mortality. The predominant form either case is sporadic with uncertain etiology. clinical features primarily motor deficits, while patients present dementia cognitive impairment. Though neuronal death a element both disorders, postmortem histopathology brain very characteristic each different from other. In molecular pathogenesis, however, significant commonality, proteinopathy (abnormal accumulation misfolded proteins), mitochondrial dysfunction oxidative stress cardinal case. These three damage mechanisms work concert, reinforcing other to drive pathology aging for diseases; interestingly, nature interactions among these similar diseases, this review attempts highlight aspects. disease, peptide amyloid beta (Aβ) responsible proteinopathy, α-synuclein plays role disease. expression levels proteins their aggregation processes modulated by reactive oxygen radicals transition metal ions manner. turn, – as oligomers or aggregated forms cause impairment apparently following mechanisms. Understanding may, therefore, help us identify putative neuroprotective strategies would be beneficial conditions. Keywords: beta, stress, α-synuclein,

Language: Английский

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α-Synuclein pathology in Parkinson’s disease and related α-synucleinopathies

Neuroscience Letters, Journal Year: 2019, Volume and Issue: 709, P. 134316 - 134316

Published: June 3, 2019

Language: Английский

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Best Practices for Generating and Using Alpha-Synuclein Pre-Formed Fibrils to Model Parkinson’s Disease in Rodents

Journal of Parkinson s Disease, Journal Year: 2018, Volume and Issue: 8(2), P. 303 - 322

Published: Jan. 30, 2018

Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting approximately one-percent of population over age sixty. Although many animal models have been developed to study this each model presents its own advantages and caveats. A unique has arisen role alpha-synuclein (aSyn) in pathogenesis PD. This involves conversion recombinant monomeric aSyn protein a fibrillar form-the pre-formed fibril (aSyn PFF)-which then injected into brain or introduced media culture. groups successfully adopted replicated PFF model, issues with generating consistent pathology reported by investigators. To improve replicability diminish these issues, The Michael J. Fox Foundation for Research (MJFF) enlisted help field leaders who performed key experiments establish provide research community guidelines practical tips improving robustness success model. Specifically, we identify pitfalls suggestions avoiding mistakes as they relate PFFs from protein, validating formation pathogenic PFFs, using vivo vitro With additional information, adoption use should present fewer challenges, resulting robust widely available

Language: Английский

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