Prion-like mechanisms in neurodegenerative diseases

Frost, Bess; Diamond, Marc I.

doi:10.1038/nrn2786

Cited by 667 publications

(541 citation statements)

References 61 publications

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“…Moreover, recent studies have shown that propagation and seeding of Aβ, tau, and α-syn in a prion-like manner might also contribute to neurodegeneration [22][23][24][25][26][27][28]. Remarkably, there is also evidence that these various protein aggregates can interact with each other [29].…”

Section: Introductionmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

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Section: Introductionmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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“…the prion protein or β-amyloid (Aβ) respectively, that are deleterious to neuronal function, as reviewed recently (Frost and Diamond, 2009). However, prionopathies are unique among neurodegenerative diseases because they are infectious.…”

Section: Micrornas and Prion Diseasementioning

confidence: 99%

“…The pathogenic isoform of the cellular PrP C , or a closely related molecule, is the causative agent of transmissible spongiform encephalopathies (TSE), that comprise a group of neurodegenerative diseases including bovine spongiform encephalopathy (BSE) in cattle, Scrapie in sheep, and Creutzfeldt-Jakob disease (CJD) in humans. Although recent studies have highlighted prion-like mechanisms of propagation of protein misfolding in other neurodegenerative diseases, such as AD (Frost and Diamond, 2009), the molecular mechanisms underlying prion-induced neurodegeneration, which coincides with neuronal loss and leads to death of the host, remains to be clearly defined.…”

Section: Micrornas and Prion Diseasementioning

confidence: 99%

MicroRNAs as a molecular basis for mental retardation, Alzheimer's and prion diseases

Provost¹

2010

Brain Research

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MicroRNAs (miRNAs) are small, ~21-to 23-nucleotide (nt) non-coding RNA species that act as key regulators of gene expression along a central and well-defined cellular process known as RNA silencing, and involving the recognition and translational control of specific messenger RNA (mRNAs). Generated through the well-orchestrated and sequential processing of miRNA precursor molecules, mature miRNAs are subsequently incorporated into miRNA-containing ribonucleoprotein effector complexes to regulate mRNA translation through the recognition of specific binding sites of imperfect complementarity located mainly in the 3′ untranslated region. Predicted to regulate up to 90% of the genes in humans, miRNAs may thus control cellular processes in all cells and tissues of the human body. Likely to play a central role in health and disease, a dysfunctional miRNA-based regulation of gene expression may represent the main etiologic factor underlying diseases affecting major organs, such as the brain. In this review article, the molecular mechanisms underlying the role and function of miRNAs in the regulation of genes involved in neurological and neurodegenerative diseases will be discussed, with a focus on the fragile X syndrome, Alzheimer's disease (AD) and prion disease.

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“…This process can be replicated in vitro by subjecting prions to a cyclic process of fibril fragmentation and fibril growth, demonstrating that autocatalytic seeded aggregation is the molecular basis of prion replication [23,24]. Recent data indicate that prion-like replication can occur in many, if not all, amyloid diseases [25,26]. Inoculating young AD model mice with brain homogenate from late-stage disease mice accelerates their disease progression [27].…”

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confidence: 99%

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Bieschke

2013

Neurotherapeutics

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Protein misfolding disorders, such as Alzheimer's disease and Parkinson's disease, have in common that a protein accumulates in an insoluble form in the affected tissue. The process of aggregation follows a mechanism of seeded polymerization. Although the toxic species is still not well defined, the process, rather than the end product, of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on depleting aggregation intermediates rather than on large fibrillar aggregates. Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG), the main polyphenol in Camilla sinensis, binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead, it promotes the formation of stable, spherical aggregates. These spherical aggregates are not cytotoxic, have a lower β-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, epi-gallocatechine-3-gallate remodels amyloid fibrils into aggregates with the same properties. Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Roccella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the Alzheimer's disease-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide. These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes.

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Prion-like mechanisms in neurodegenerative diseases

Cited by 667 publications

References 61 publications

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

MicroRNAs as a molecular basis for mental retardation, Alzheimer's and prion diseases

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

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