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Ceftriaxone blocks the polymerization of ?-synuclein and exerts neuroprotective effects in vitro.

ABSTRACT: The ?-lactam antibiotic ceftriaxone was suggested as a therapeutic agent in several neurodegenerative disorders, either for its ability to counteract glutamate-mediated toxicity, as in cerebral ischemia, or for its ability to enhance the degradation of misfolded proteins, as in Alexander's disease. Recently, the efficacy of ceftriaxone in neuroprotection of dopaminergic neurons in a rat model of Parkinson's disease was documented. However, which characteristics of ceftriaxone mediate its therapeutic effects remains unclear. Since, at the molecular level, neuronal ?-synuclein inclusions and pathological ?-synuclein transmission play a leading role in initiation of Parkinson-like neurodegeneration, we thought of investigating, by circular dichroism spectroscopy, the capability of ceftriaxone to interact with ?-synuclein. We found that ceftriaxone binds with good affinity to ?-synuclein and blocks its in vitro polymerization. Considering this finding, we also documented that ceftriaxone exerts neuroprotective action in an in vitro model of Parkinson's disease. Our data, in addition to the findings on neuroprotective activity of ceftriaxone on Parkinson-like neurodegeneration in vivo, indicates ceftriaxone as a potential agent in treatment of Parkinson's disease.

SUBMITTER: Ruzza P

PROVIDER: S-EPMC3894726 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Ceftriaxone blocks the polymerization of α-synuclein and exerts neuroprotective effects in vitro.

Ruzza Paolo P Siligardi Giuliano G Hussain Rohanah R Marchiani Anna A Islami Mehmet M Bubacco Luigi L Delogu Giovanna G Fabbri Davide D Dettori Maria A MA Sechi Mario M Pala Nicolino N Spissu Ylenia Y Migheli Rossana R Serra Pier A PA Sechi GianPietro G

ACS chemical neuroscience 20131024 1

The β-lactam antibiotic ceftriaxone was suggested as a therapeutic agent in several neurodegenerative disorders, either for its ability to counteract glutamate-mediated toxicity, as in cerebral ischemia, or for its ability to enhance the degradation of misfolded proteins, as in Alexander's disease. Recently, the efficacy of ceftriaxone in neuroprotection of dopaminergic neurons in a rat model of Parkinson's disease was documented. However, which characteristics of ceftriaxone mediate its therape ...[more]

PMID: 24099687

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Project description:Misfolded ?-synuclein is a key factor in the pathogenesis of Parkinson's disease (PD). However, knowledge about a physiological role for the native, unfolded ?-synuclein is limited. Using brains of mice lacking ?-, ?-, and ?-synuclein, we report that extracellular monomeric ?-synuclein enters neurons and localizes to mitochondria, interacts with ATP synthase subunit ?, and modulates ATP synthase function. Using a combination of biochemical, live-cell imaging and mitochondrial respiration analysis, we found that brain mitochondria of ?-, ?-, and ?-synuclein knock-out mice are uncoupled, as characterized by increased mitochondrial respiration and reduced mitochondrial membrane potential. Furthermore, synuclein deficiency results in reduced ATP synthase efficiency and lower ATP levels. Exogenous application of low unfolded ?-synuclein concentrations is able to increase the ATP synthase activity that rescues the mitochondrial phenotypes observed in synuclein deficiency. Overall, the data suggest that ?-synuclein is a previously unrecognized physiological regulator of mitochondrial bioenergetics through its ability to interact with ATP synthase and increase its efficiency. This may be of particular importance in times of stress or PD mutations leading to energy depletion and neuronal cell toxicity. SIGNIFICANCE STATEMENT:Misfolded ?-synuclein aggregations in the form of Lewy bodies have been shown to be a pathological hallmark in histological staining of Parkinson's disease (PD) patient brains. It is known that misfolded ?-synuclein is a key driver in PD pathogenesis, but the physiological role of unfolded monomeric ?-synuclein remains unclear. Using neuronal cocultures and isolated brain mitochondria of ?-, ?-, and ?-synuclein knock-out mice and monomeric ?-synuclein, this current study shows that ?-synuclein in its unfolded monomeric form improves ATP synthase efficiency and mitochondrial function. The ability of monomeric ?-synuclein to enhance ATP synthase efficiency under physiological conditions may be of importance when ?-synuclein undergoes the misfolding and aggregation reported in PD.

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Ceftriaxone blocks the polymerization of ?-synuclein and exerts neuroprotective effects in vitro.

Publications

Ceftriaxone blocks the polymerization of α-synuclein and exerts neuroprotective effects in vitro.

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