Dataset Information

The N-terminal Set-? Protein Isoform Induces Neuronal Death.

ABSTRACT: Set-? protein plays different roles in neurons, but the diversity of Set-? neuronal isoforms and their functions have not been characterized. The expression and subcellular localization of Set-? are altered in Alzheimer disease, cleavage of Set-? leads to neuronal death after stroke, and the full-length Set-? regulates retinal ganglion cell (RGC) and hippocampal neuron axon growth and regeneration in a subcellular localization-dependent manner. Here we used various biochemical approaches to investigate Set-? isoforms and their role in the CNS, using the same type of neurons, RGCs, across studies. We found multiple alternatively spliced isoforms expressed from the Set locus in purified RGCs. Set transcripts containing the Set-?-specific exon were the most highly expressed isoforms. We also identified a novel, alternatively spliced Set-? transcript lacking the nuclear localization signal and demonstrated that the full-length (?39-kDa) Set-? is localized predominantly in the nucleus, whereas a shorter (?25-kDa) Set-? isoform is localized predominantly in the cytoplasm. Finally, we show that an N-terminal Set-? cleavage product can induce neuronal death.

SUBMITTER: Trakhtenberg EF

PROVIDER: S-EPMC4505589 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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The N-terminal Set-β Protein Isoform Induces Neuronal Death.

Trakhtenberg Ephraim F EF Morkin Melina I MI Patel Karan H KH Fernandez Stephanie G SG Sang Alan A Shaw Peter P Liu Xiongfei X Wang Yan Y Mlacker Gregory M GM Gao Han H Velmeshev Dmitry D Dombrowski Susan M SM Vitek Michael P MP Goldberg Jeffrey L JL

The Journal of biological chemistry 20150401 21

Set-β protein plays different roles in neurons, but the diversity of Set-β neuronal isoforms and their functions have not been characterized. The expression and subcellular localization of Set-β are altered in Alzheimer disease, cleavage of Set-β leads to neuronal death after stroke, and the full-length Set-β regulates retinal ganglion cell (RGC) and hippocampal neuron axon growth and regeneration in a subcellular localization-dependent manner. Here we used various biochemical approaches to inve ...[more]

PMID: 25833944

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Project description:Background & aimsIn cirrhosis, astrocytic swelling is believed to be the principal mechanism of ammonia neurotoxicity leading to hepatic encephalopathy (HE). The role of neuronal dysfunction in HE is not clear. We aimed to explore the impact of hyperammonaemia on mitochondrial function in primary co-cultures of neurons and astrocytes and in acute brain slices of cirrhotic rats using live cell imaging.MethodsTo primary cocultures of astrocytes and neurons, low concentrations (1 and 5 μM) of NH4Cl were applied. In rats with bile duct ligation (BDL)-induced cirrhosis, a model known to induce hyperammonaemia and minimal HE, acute brain slices were studied. One group of BDL rats was treated twice daily with the ammonia scavenger ornithine phenylacetate (OP; 0.3 g/kg). Fluorescence measurements of changes in mitochondrial membrane potential (Δψm), cytosolic and mitochondrial reactive oxygen species (ROS) production, lipid peroxidation (LP) rates, and cell viability were performed using confocal microscopy.ResultsNeuronal cultures treated with NH4Cl exhibited mitochondrial dysfunction, ROS overproduction, and reduced cell viability (27.8 ± 2.3% and 41.5 ± 3.7%, respectively) compared with untreated cultures (15.7 ± 1.0%, both p <0.0001). BDL led to increased cerebral LP (p = 0.0003) and cytosolic ROS generation (p <0.0001), which was restored by OP (both p <0.0001). Mitochondrial function was severely compromised in BDL, resulting in hyperpolarisation of Δψm with consequent overconsumption of adenosine triphosphate and augmentation of mitochondrial ROS production. Administration of OP restored Δψm. In BDL animals, neuronal loss was observed in hippocampal areas, which was partially prevented by OP.ConclusionsOur results elucidate that low-grade hyperammonaemia in cirrhosis can severely impact on brain mitochondrial function. Profound neuronal injury was observed in hyperammonaemic conditions, which was partially reversible by OP. This points towards a novel mechanism of HE development.Lay summaryThe impact of hyperammonaemia, a common finding in patients with liver cirrhosis, on brain mitochondrial function was investigated in this study. The results show that ammonia in concentrations commonly seen in patients induces severe mitochondrial dysfunction, overproduction of damaging oxygen molecules, and profound injury and death of neurons in rat brain cells. These findings point towards a novel mechanism of ammonia-induced brain injury in liver failure and potential novel therapeutic targets.

Dataset Information

The N-terminal Set-? Protein Isoform Induces Neuronal Death.

Publications

The N-terminal Set-β Protein Isoform Induces Neuronal Death.

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