A Blood-Brain Barrier (BBB) Disrupter Is Also a Potent α-Synuclein (α-syn) Aggregation Inhibitor

Shaltiel-Karyo, Ronit; Frenkel-Pinter, Moran; Rockenstein, Edward; Patrick, Christina; Levy‐Sakin, Michal; Schiller, Abigail; Egoz-Matia, Nirit; Masliah, Eliezer; Segal, Daniel; Gazit, Ehud

doi:10.1074/jbc.m112.434787

Cited by 84 publications

(42 citation statements)

References 40 publications

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“…The α‐syn protein was incubated with or without CP‐2 for different time intervals at 37 °C with constant shaking. The samples were then centrifuged and the supernatant containing the monomers and soluble α‐syn oligomers was separated from the pellet that contained the larger fibrils . The samples were then analyzed by CD spectroscopy after reconstitution of the pellet in the same volume of PB (phosphate buffer, 10 m m , pH 7.4).…”

Section: Resultsmentioning

confidence: 99%

Self‐Assembled Cyclic d,l‐α‐Peptides as Generic Conformational Inhibitors of the α‐Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies

Chemerovski-Glikman

Rozentur-Shkop

Richman

et al. 2016

Chemistry A European J

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Many peptides and proteins with large sequences and structural differences self-assemble into disease-causing amyloids that share very similar biochemical and biophysical characteristics, which may contribute to their cross-interaction. Here, we demonstrate how the self-assembled, cyclic d,l-α-peptide CP-2, which has similar structural and functional properties to those of amyloids, acts as a generic inhibitor of the Parkinson's disease associated α-synuclein (α-syn) aggregation to toxic oligomers by an "off-pathway" mechanism. We show that CP-2 interacts with the N-terminal and the non-amyloid-β component region of α-syn, which are responsible for α-syn's membrane intercalation and self-assembly, thus changing the overall conformation of α-syn. CP-2 also remodels α-syn fibrils to nontoxic amorphous species and permeates cells through endosomes/lysosomes to reduce the accumulation and toxicity of intracellular α-syn in neuronal cells overexpressing α-syn. Our studies suggest that targeting the common structural conformation of amyloids may be a promising approach for developing new therapeutics for amyloidogenic diseases.

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Section: Resultsmentioning

confidence: 99%

Self‐Assembled Cyclic d,l‐α‐Peptides as Generic Conformational Inhibitors of the α‐Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies

Chemerovski-Glikman

Rozentur-Shkop

Richman

et al. 2016

Chemistry A European J

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“…Involvement of brain interfaces, such as BBB and BCSFB, has been implicated in various neurodegenerative diseases, such as AD (Deane and Zlokovic, 2007;Zisper et al, 2007;Agyare et al, 2013;Burgmans et al, 2013), PD (Shaltiel-Karyo, et al, 2013), motor neuron disease (Garbuzova-Davis et al, 2007), and MS (Minagar and Alexander, 2003;van Horssen et al, 2007;Basivireddy et al, 2013). Modulation of the BBB permeability has also been reported in stroke, TBI, epilepsy (Abbott and Friedman, 2012;de Vries et al, 2012), autism, schizophrenia and other psychiatric disorders (Shalev et al, 2009;Palmer, 2010), GWI (Amourette et al, 2009), and edema, hypoxic-reoxygenation, or ischemic conditions (Deli et al, 2005;Kaur and Ling, 2008).…”

Section: Brain Barriers and Cns Diseasesmentioning

confidence: 99%

Blood–Brain Barrier Damage and Dysfunction by Chemical Toxicity

Gupta

Pitt

Zaja‐Milatovic

2015

Handbook of Toxicology of Chemical Warfare Agents

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“…This methodology, however, has only achieved favorable results with in-vitro models 61, 62 , and no animal studies have been conducted. Other molecules that have shown some promising results in inhibiting α-syn aggregation include dopamine 63 , mannitol 64 , catechol-o-methyltransferase inhibitors 65 , cinnamon extract 66 , and ring-fused pyridones (small organic molecules with antibacterial activity) 67 .…”

Section: Potential Therapeutic Targets In Msamentioning

confidence: 99%

Novel therapeutic approaches in multiple system atrophy

Palma

2014

Clin Auton Res

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Multiple system atrophy (MSA) is a sporadic, adult onset, relentlessly, progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism, cerebellar dysfunction, pyramidal signs, or combinations thereof. Treatments that can halt or reverse the progression of MSA have not yet been identified. MSA is neuropathologically defined by the presence of α-synuclein–containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic α-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprise cell-to-cell transmission of α-synuclein in a prion-like manner, α-synuclein aggregation, increased oxidative stress, abnormal expression of tubulin proteins, decreased expression of neurotrophic factors, excitotoxicity and microglial activation, and neuroinflammation. In an attempt to block each of these pathogenic mechanisms, several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA. These include sertraline, paroxetine, and lithium, which hamper arrival of α-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflamatory drugs, which inhibit α-synuclein aggregation in oligodendrocytes; riluzole, rasagiline, fluoxetine and mesenchimal stem cells, which exert neuroprotective actions; and minocycline and intravenous immunoglobulins, which reduce neuroinflammation and microglial activation. These and other potential therapeutic strategies for MSA are summarized in this review.

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A Blood-Brain Barrier (BBB) Disrupter Is Also a Potent α-Synuclein (α-syn) Aggregation Inhibitor

Cited by 84 publications

References 40 publications

Self‐Assembled Cyclic d,l‐α‐Peptides as Generic Conformational Inhibitors of the α‐Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies

Self‐Assembled Cyclic d,l‐α‐Peptides as Generic Conformational Inhibitors of the α‐Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies

Blood–Brain Barrier Damage and Dysfunction by Chemical Toxicity

Novel therapeutic approaches in multiple system atrophy

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