The aggregation of amyloidogenic proteins is a pathological hallmark of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In these diseases, oligomeric intermediates or toxic aggregates of amyloids cause neuronal damage and degeneration. Despite the substantial effort made over recent decades to implement therapeutic interventions, these neurodegenerative diseases are not yet understood at the molecular level. In many cases, multiple disease-causing amyloids overlap in a sole pathological feature, or a sole disease-causing amyloid represents multiple pathological features. Various amyloid pathologies can coexist in the same brain with or without clinical presentation and may even occur in individuals without disease. From sparse data, speculation has arisen regarding the coaggregation of amyloids with disparate amyloid species and other biomolecules, which are the same characteristics that make diagnostics and drug development challenging. However, advances in research related to biomolecular condensates and structural analysis have been used to overcome some of these challenges. Considering the development of these resources and techniques, herein we review the cross-seeding of amyloidosis, for example, involving the amyloids amyloid β, tau, α-synuclein, and human islet amyloid polypeptide, and their cross-inhibition by transthyretin and BRICHOS. The interplay of nucleic acid-binding proteins, such as prions, TAR DNA-binding protein 43, fused in sarcoma/translated in liposarcoma, and fragile X mental retardation polyglycine, with nucleic acids in the pathology of neurodegeneration are also described, and we thereby highlight the potential clinical applications in central nervous system therapy.
L'aggregazione di proteine amiloidogeniche è un segno distintivo patologico di varie malattie neurodegenerative, tra cui il morbo di Alzheimer, il morbo di Parkinson e la sclerosi laterale amiotrofica. In queste malattie intermedi oligomerici o aggregati tossici di amiloidi causano danni e degenerazione neuronale. Nonostante i notevoli sforzi compiuti negli ultimi decenni per sviluppare interventi terapeutici, queste malattie neurodegenerative non sono ancora comprese a livello molecolare. In molti casi più amiloidi che causano la malattia si sovrappongono in un'unica caratteristica patologica o in un'unica amiloide che causa la malattia, rappresentando più caratteristiche patologiche. Diverse patologie amiloidi possono coesistere nello stesso cervello con o senza manifestazione clinica e possono anche verificarsi in individui senza malattia. Sulla base di dati scarsi, sono sorte speculazioni sulla coaggregazione dell'amiloide con diverse specie amiloidi e altre biomolecole, che sono le stesse caratteristiche che rendono difficile la diagnostica e lo sviluppo di farmaci. Tuttavia, i progressi della ricerca sui condensati biomolecolari e l'analisi strutturale sono stati utilizzati per superare alcune di queste sfide. Considerando lo sviluppo di queste risorse e tecniche, in questa review esaminiamo il cross-seeding dell'amiloidosi, che coinvolge, ad esempio, l'amiloide β, la tau, l'α-sinucleina e il polipeptide amiloide dell'isoletta umana (IAPP) e la loro inibizione incrociata da parte della transtiretina e del BRICHOS. Viene inoltre descritta l'interazione delle proteine che legano gli acidi nucleici (come i prioni, la TAR DNA-binding protein 43, la proteina fusa nel sarcoma/tradotta nel liposarcoma, e la poliglicina del ritardo mentale dell'X fragile) con gli acidi nucleici nella patologia della neurodegenerazione, evidenziando così le potenziali applicazioni cliniche nella terapia del sistema nervoso centrale.
Aggregati amiloidi ed interazione con biomolecole rilevanti nella neurodegenerazione
DARIO, FLAVIA
2022/2023
Abstract
The aggregation of amyloidogenic proteins is a pathological hallmark of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In these diseases, oligomeric intermediates or toxic aggregates of amyloids cause neuronal damage and degeneration. Despite the substantial effort made over recent decades to implement therapeutic interventions, these neurodegenerative diseases are not yet understood at the molecular level. In many cases, multiple disease-causing amyloids overlap in a sole pathological feature, or a sole disease-causing amyloid represents multiple pathological features. Various amyloid pathologies can coexist in the same brain with or without clinical presentation and may even occur in individuals without disease. From sparse data, speculation has arisen regarding the coaggregation of amyloids with disparate amyloid species and other biomolecules, which are the same characteristics that make diagnostics and drug development challenging. However, advances in research related to biomolecular condensates and structural analysis have been used to overcome some of these challenges. Considering the development of these resources and techniques, herein we review the cross-seeding of amyloidosis, for example, involving the amyloids amyloid β, tau, α-synuclein, and human islet amyloid polypeptide, and their cross-inhibition by transthyretin and BRICHOS. The interplay of nucleic acid-binding proteins, such as prions, TAR DNA-binding protein 43, fused in sarcoma/translated in liposarcoma, and fragile X mental retardation polyglycine, with nucleic acids in the pathology of neurodegeneration are also described, and we thereby highlight the potential clinical applications in central nervous system therapy.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12075/14124