Protein Misfolding and Neurodegeneration

Soto, Claudio; Estrada, Lisbell D.

doi:10.1001/archneurol.2007.56

Cited by 306 publications

(211 citation statements)

References 64 publications

(106 reference statements)

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“…7C, F). The presence of polyubiquitinated aggregates is an hallmark of neurodegenerative diseases [37,38] including Alzheimer's Disease, Parkinson's Disease and Amyotrophic Lateral Sclerosis (ALS). Thus we have investigated Epoxomicin's effects on an in vitro model of ALS.…”

Section: β-Estradiol and Epoxomicin Impact On Primary Spinal Cord Culmentioning

confidence: 99%

Protein repertoire impact of Ubiquitin–Proteasome System impairment: Insight into the protective role of beta-estradiol

D'Alessandro¹,

D’Aguanno²,

Cencioni³

et al. 2012

Journal of Proteomics

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The Ubiquitin-Proteasome System (UPS) and the Autophagy-Lysosome Pathways (ALP) are key mechanisms for cellular homeostasis sustenance and protein clearance. A wide number of Neurodegenerative Diseases (NDs) are tied with UPS impairment and have been also described as proteinopathies caused by aggregate-prone proteins, not efficiently removed by proteasome.Despite the large knowledge on proteasome biological role, molecular mechanisms associated with its impairment are still blur. We have pursued a comprehensive proteomic investigation to evaluate the phenotypic rearrangements in protein repertoires associated with a UPS blockage. Unsupervised meta-analysis of the collected proteomic data revealed that all the identified proteins relate each other in a functional network centered on beta-estradiol. Moreover we showed that treatment of cells with beta-estradiol resulted in aggregate removal and increased cell survival due to activation of the autophagic pathway. Our data may provide the molecular basis for the use of beta-estradiol in neurodegenerative disorders by induction of protein aggregate removal.

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Section: β-Estradiol and Epoxomicin Impact On Primary Spinal Cord Culmentioning

confidence: 99%

Protein repertoire impact of Ubiquitin–Proteasome System impairment: Insight into the protective role of beta-estradiol

D'Alessandro¹,

D’Aguanno²,

Cencioni³

et al. 2012

Journal of Proteomics

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“…Although accounting for only a small percentage of all ALS cases, SOD1 mutations represent one of the main known causes of the disease. The similar symptoms and pathology of familial and sporadic ALS suggest common disease mechanisms and the potential for related therapeutic strategies (1)(2)(3). The mechanisms by which mutant SOD1 causes ALS are not known; however, extensive evidence supports a toxic gain of function due to increased aggregation of mutant protein.…”

mentioning

confidence: 99%

“…The mechanisms by which mutant SOD1 causes ALS are not known; however, extensive evidence supports a toxic gain of function due to increased aggregation of mutant protein. Misfolding and aggregation of diverse proteins are observed in numerous diseases, including other neurodegenerative diseases such as Alzheimer's, Huntington, and prion diseases (1,2). Amyloid is a type of aggregate structure formed by many disease-associated proteins, and perhaps by all proteins, often under destabilizing conditions (4).…”

mentioning

confidence: 99%

Decreased stability and increased formation of soluble aggregates by immature superoxide dismutase do not account for disease severity in ALS

Vassall¹,

Stubbs²,

Primmer³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

100

145

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Protein aggregation is a hallmark of many diseases, including amyotrophic lateral sclerosis (ALS), where aggregation of Cu/Zn superoxide dismutase (SOD1) is implicated in causing neurodegeneration. Recent studies have suggested that destabilization and aggregation of the most immature form of SOD1, the disulfide-reduced, unmetallated (apo) protein is particularly important in causing ALS. We report herein in depth analyses of the effects of chemically and structurally diverse ALS-associated mutations on the stability and aggregation of reduced apo SOD1. In contrast with previous studies, we find that various reduced apo SOD1 mutants undergo highly reversible thermal denaturation with little aggregation, enabling quantitative thermodynamic stability analyses. In the absence of ALS-associated mutations, reduced apo SOD1 is marginally stable but predominantly folded. Mutations generally result in slight decreases to substantial increases in the fraction of unfolded protein. Calorimetry, ultracentrifugation, and light scattering show that all mutations enhance aggregation propensity, with the effects varying widely, from subtle increases in most cases, to pronounced formation of 40–100 nm soluble aggregates by A4V, a mutation that is associated with particularly short disease duration. Interestingly, although there is a correlation between observed aggregation and stability, there is minimal to no correlation between observed aggregation, predicted aggregation propensity, and disease characteristics. These findings suggest that reduced apo SOD1 does not play a dominant role in modulating disease. Rather, additional and/or multiple forms of SOD1 and additional biophysical and biological factors are needed to account for the toxicity of mutant SOD1 in ALS.

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“…Many neurodegenerative diseases involve accumulation of intracellular aggregates of misfolded protein, implying that defects in protein processing may be linked to their development and pathogenesis (1,2). Molecular genetic studies have identified a number of intracellular proteins involved in these processes, and these may ultimately prove useful as targets for therapeutic drug development (3).…”

mentioning

confidence: 99%

Functional Protein Delivery into Neurons Using Polymeric Nanoparticles

Hasadsri

Kreuter

Hashimoto³

et al. 2009

Journal of Biological Chemistry

121

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An efficient route for delivering specific proteins and peptides into neurons could greatly accelerate the development of therapies for various diseases, especially those involving intracellular defects such as Parkinson disease. Here we report the novel use of polybutylcyanoacrylate nanoparticles for delivery of intact, functional proteins into neurons and neuronal cell lines. Uptake of these particles is primarily dependent on endocytosis via the low density lipoprotein receptor. The nanoparticles are rapidly turned over and display minimal toxicity to cultured neurons. Delivery of three different functional cargo proteins is demonstrated. When primary neuronal cultures are treated with recombinant Escherichia coli ␤-galactosidase as nanoparticle cargo, persistent enzyme activity is measured beyond the period of nanoparticle degradation. Delivery of the small GTPase rhoG induces neurite outgrowth and differentiation in PC12 cells. Finally, a monoclonal antibody directed against synuclein is capable of interacting with endogenous ␣-synuclein in cultured neurons following delivery via nanoparticles. Polybutylcyanoacrylate nanoparticles are thus useful for intracellular protein delivery in vitro and have potential as carriers of therapeutic proteins for treatment of neuronal disorders in vivo.

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Protein Misfolding and Neurodegeneration

Cited by 306 publications

References 64 publications

Protein repertoire impact of Ubiquitin–Proteasome System impairment: Insight into the protective role of beta-estradiol

Protein repertoire impact of Ubiquitin–Proteasome System impairment: Insight into the protective role of beta-estradiol

Decreased stability and increased formation of soluble aggregates by immature superoxide dismutase do not account for disease severity in ALS

Functional Protein Delivery into Neurons Using Polymeric Nanoparticles

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