MODELS OF AMYLOID SEEDING IN ALZHEIMER'S DISEASE AND SCRAPIE: Mechanistic Truths and Physiological Consequences of the Time-Dependent Solubility of Amyloid Proteins

Harper, James D.; Lansbury, Peter T.

doi:10.1146/annurev.biochem.66.1.385

Cited by 1,525 publications

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“…Protein aggregation is a common hallmark of neurodegenerative disease (Harper & Lansbury, 1997; Trojanowski et al , 1998; Koo et al , 1999; Aguzzi & O'Connor, 2010) although the mechanisms of toxicity remain poorly understood. Different neurodegenerative diseases, or their subtypes, are often distinguished by the specific patterns of protein aggregation.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

et al. 2017

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Neuronal inclusions of aggregated RNA‐binding protein fused in sarcoma (FUS) are hallmarks of ALS and frontotemporal dementia subtypes. Intriguingly, FUS's nearly uncharged, aggregation‐prone, yeast prion‐like, low sequence‐complexity domain (LC) is known to be targeted for phosphorylation. Here we map in vitro and in‐cell phosphorylation sites across FUS LC. We show that both phosphorylation and phosphomimetic variants reduce its aggregation‐prone/prion‐like character, disrupting FUS phase separation in the presence of RNA or salt and reducing FUS propensity to aggregate. Nuclear magnetic resonance spectroscopy demonstrates the intrinsically disordered structure of FUS LC is preserved after phosphorylation; however, transient domain collapse and self‐interaction are reduced by phosphomimetics. Moreover, we show that phosphomimetic FUS reduces aggregation in human and yeast cell models, and can ameliorate FUS‐associated cytotoxicity. Hence, post‐translational modification may be a mechanism by which cells control physiological assembly and prevent pathological protein aggregation, suggesting a potential treatment pathway amenable to pharmacologic modulation.

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Section: Introductionmentioning

confidence: 99%

Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

et al. 2017

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“…The misfolding of a unique peptide or protein into b-sheet-rich fibrous structures is proposed to be a key step in the onset and development of these diseases [3,5]. The amyloid deposits cause cell dysfunction, death, and subsequently severe impairment in tissues of patients.…”

Section: Introductionmentioning

confidence: 99%

Ganglioside‐induced amyloid formation by human islet amyloid polypeptide in lipid rafts

Wakabayashi¹,

Matsuzaki²

2009

FEBS Letters

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Edited by Jesus Avila Keywords:Human islet amyloid polypeptide Amyloid fibril Ganglioside Cholesterol Lipid raft a b s t r a c t Human islet amyloid polypeptide (hIAPP) is the primary component of the amyloid deposits found in the pancreatic islets of patients with type 2 diabetes mellitus. However, it is unknown how amyloid fibrils are formed in vivo. In this study, we demonstrate that gangliosides play an essential role in the formation of amyloid deposits by hIAPP on plasma membranes. Amyloid fibrils accumulated in ganglioside-and cholesterol-rich microscopic domains ('lipid rafts'). The depletion of gangliosides or cholesterol significantly reduced the amount of amyloid deposited. These results clearly showed that the formation of amyloid fibrils was mediated by gangliosides in lipid rafts.

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“…Some studies concentrated on the central sequence of Ab peptide, suggesting that Ab [14][15][16][17][18][19][20][21][22][23] [12] and Ab [16][17][18][19][20][21][22] [13] are the fibril-generating peptide fragments, other study indicated that the Ab 36-42 fragment could form very stable fibril with highly ordered structure and is a key factor determining the aggregation of Ab 1-42 [14]. This renders us to reconsider why only Ab 40 and Ab 42 peptides are neurotoxic and why Ab 42 aggregates into fibrils faster than Ab 40 [5]. a-Syn is another amyloidogenic protein of great interest that is closely associated with the Lewy bodies in Parkinson disease [15,16].…”

Section: Introductionmentioning

confidence: 99%

Acceleration of α‐synuclein aggregation by homologous peptides

Zhang

et al. 2006

FEBS Letters

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a-Synuclein (a-Syn), amyloid b-protein and prion protein are among the amyloidogenic proteins that are associated with the neurodegenerative diseases. These three proteins share a homologous region with a consensus sequence mainly consisting of glycine, alanine and valine residues (accordingly named as the GAV motif), which was proposed to be the critical core for the fibrillization and cytotoxicity. To understand the role of the GAV motif in protein amyloidogenesis, we studied the effects of the homologous peptides corresponding to the sequence of GAV motif region (residues 66-74) on a-Syn aggregation. The result shows that these peptides can promote fibrillization of wild-type a-Syn and induce that of the charge-incorporated mutants but not the GAV-deficient a-Syn mutant. The acceleration of a-Syn aggregation by the homologous peptides is under a sequence-specific manner. The interplay between the GAV peptide and the core regions in a-Syn may accelerate the aggregation process and stabilize the fibrils. This finding provides clues for developing peptide mimics that could promote transforming the toxic oligomers or protofibrils into the inert mature fibrils.

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MODELS OF AMYLOID SEEDING IN ALZHEIMER'S DISEASE AND SCRAPIE: Mechanistic Truths and Physiological Consequences of the Time-Dependent Solubility of Amyloid Proteins

Cited by 1,525 publications

References 94 publications

Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

Ganglioside‐induced amyloid formation by human islet amyloid polypeptide in lipid rafts

Acceleration of α‐synuclein aggregation by homologous peptides

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