Amyloid assembly and disassembly

Chuang, Edward; Hori, Acacia M; Hesketh, Christina D.; Shorter, James

doi:10.1242/jcs.189928

Cited by 163 publications

(182 citation statements)

References 356 publications

(593 reference statements)

Supporting

Mentioning

181

Contrasting

Order By: Relevance

“…In order to prevent these proteins from aggregating, they are subject to tight regulation. However, if this process becomes dysregulated, it may cause fatal neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease (Blancas-Mejia and Ramirez-Alvarado 2013; Chuang et al 2018). Thus, amyloidogenesis does not necessarily require mutations in these metastable proteins to occur.…”

Section: Small Heat Shock Proteins As Modifiers Of Aggregation-prone mentioning

confidence: 99%

Small heat shock proteins in neurodegenerative diseases

Vendredy

Adriaenssens

Timmerman

2020

Cell Stress and Chaperones

View full text Add to dashboard Cite

Small heat shock proteins are ubiquitously expressed chaperones, yet mutations in some of them cause tissue-specific diseases.Here, we will discuss how small heat shock proteins give rise to neurodegenerative disorders themselves while we will also highlight how these proteins can fulfil protective functions in neurodegenerative disorders caused by protein aggregation. The first half of this paper will be focused on how mutations in HSPB1, HSPB3, and HSPB8 are linked to inherited peripheral neuropathies like Charcot-Marie-Tooth (CMT) disease and distal hereditary motor neuropathy (dHMN). The second part of the paper will discuss how small heat shock proteins are linked to neurodegenerative disorders like Alzheimer's, Parkinson's, and Huntington's disease.

show abstract

Section: Small Heat Shock Proteins As Modifiers Of Aggregation-prone mentioning

confidence: 99%

Small heat shock proteins in neurodegenerative diseases

Vendredy

Adriaenssens

Timmerman

2020

Cell Stress and Chaperones

View full text Add to dashboard Cite

show abstract

“…α-Syn misfolds into toxic oligomers and amyloid fibrils, accumulating in characteristic Lewy bodies in the cytoplasm of dopaminergic neurons that degenerate in PD (Araki et al, 2019;Henderson et al, 2019;Shahmoradian et al, 2019). Indeed, protein misfolding and aggregation unite a spectrum of fatal neurodegenerative diseases (Chuang et al, 2018). Thus, it is important to develop therapeutics that directly antagonize the underlying toxic protein-misfolding events in neurodegenerative disease.…”

Section: Introductionmentioning

confidence: 99%

Tuning Hsp104 specificity to selectively detoxify α-synuclein

Mack

Kim

Jackrel³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Hsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate toxic misfolding of α-synuclein, TDP-43, and FUS implicated in fatal neurodegenerative disorders. Though potent disaggregases, these enhanced Hsp104 variants lack substrate specificity, and can have unfavorable off-target effects. Here, to lessen off-target effects, we engineer substrate-specific Hsp104 variants. By altering Hsp104 pore loops that engage substrate, we disambiguate Hsp104 variants that selectively suppress α-synuclein toxicity but not TDP-43 or FUS toxicity. Remarkably, αsynuclein-specific Hsp104 variants emerge that mitigate α-synuclein toxicity via distinct ATPase-dependent mechanisms, involving α-synuclein disaggregation or detoxification of α-synuclein conformers without disaggregation. Importantly, both types of α-synucleinspecific Hsp104 variant reduce dopaminergic neurodegeneration in a C. elegans model of Parkinson's disease more effectively than non-specific variants. We suggest that increasing the substrate specificity of enhanced disaggregases could be applied broadly to tailor therapeutics for neurodegenerative disease.

show abstract

“…With steel's strength and silk's stiffness, these insoluble fibers resist digestion . While some function beneficially, most induce two diseases: systemic forms found at distant sites that deposit extracellularly, and localized forms that deposit intra‐ and/or extracellularly in the same tissue …”

Section: Introductionmentioning

confidence: 99%

“…3 While some function beneficially, most induce two diseases: systemic forms found at distant sites that deposit extracellularly, and localized forms that deposit intraand/or extracellularly in the same tissue. 2,4,5 Localized amyloidoses range from Alzheimer's extracellular deposits to Huntington's intracellular tangles to rare amyloidoma masses. 4,[6][7][8][9][10][11] Only 7-12% of amyloid deposition causes amyloidomas.…”

Section: Introductionmentioning

confidence: 99%

Primary cervical spine AL‐κ amyloidoma: A case report and review of the literature

et al. 2019

View full text Add to dashboard Cite

Of the myriad of variants of amyloidoses where abnormally folded proteins damage native tissue, primary cervical spine amyloidoma represents one of the rarest forms. Since clinical presentations and imaging findings appear similar to other pathologies, including abscesses, metastatic lesions, and inflammatory lesions, a definitive diagnosis requires a biopsy with specific immunohistochemical stains. We present the first known case of primary cervical amyloid light‐chain (AL)‐κ subtype amyloidoma and compare the clinical presentations, imaging findings, treatment options, and immunohistochemical subtypes of primary, hemodialysis, and multiple myeloma cervical amyloidomas. Our case is of a 58‐year‐old man who developed neck pain radiating to the left arm with bilateral upper extremity weakness over several months. Magnetic resonance imaging revealed a circumferential C1–C2 mass extending into the neural foramina inducing severe mass effect. The patient underwent C2 laminectomy and resection of the lesion which was discovered during surgery to be completely epidural. Postoperatively, his pain and weakness improved. A complete work‐up was negative for systemic amyloidosis or inflammatory conditions. In the setting of a long clinical history of hemodialysis, this patient required specific staining and laboratory testing to correctly diagnose his primary cervical AL‐κ subtype amyloidoma. Cervical amyloidomas comprise a very small minority of amyloid pathology with an exceptional prognosis following successful surgical resection and stabilization. It is recommended these patients undergo surgical resection with appropriate characterization and a complete work‐up to rule out systemic disease.

show abstract

Amyloid assembly and disassembly

Cited by 163 publications

References 356 publications

Small heat shock proteins in neurodegenerative diseases

Small heat shock proteins in neurodegenerative diseases

Tuning Hsp104 specificity to selectively detoxify α-synuclein

Primary cervical spine AL‐κ amyloidoma: A case report and review of the literature

Contact Info

Product

Resources

About