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Shahana S. Mahajan, Ph.D Research Assistant Professor NYU School of Medicine.

Mechanisms of Neuron Death in Neurodegenerative Diseases. Shahana S. Mahajan, Ph.D Research Assistant Professor NYU School of Medicine. Central nervous system has specialized cells. A typical neuron. Neurons signal through synapses. GluR1-4.

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Shahana S. Mahajan, Ph.D Research Assistant Professor NYU School of Medicine.

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  1. Mechanisms of Neuron Death in Neurodegenerative Diseases Shahana S. Mahajan, Ph.D Research Assistant Professor NYU School of Medicine.

  2. Central nervous system has specialized cells A typical neuron

  3. Neurons signal through synapses

  4. GluR1-4 AMPA receptors are glutamate gated cationic channels AMPA receptors are homo or heterotertamers of four subunits GluR1, 2, 3 and 4

  5. Ca2+ Ca2+ R1 R1 R2 R3 R2 R3 Ca2+ Properties of AMPA heteromer depend on subunit composition GluR2 lacking GluR2 containing

  6. N Ligand binding domain Flip/Flop region TM1 TM2 TM3 TM4 NSF binding domain C RNA editing R607Q GluR2 structure

  7. N TM1 TM2 TM3 TM4 Q C GluR2Q Unedited GluR2 (mutated) Unedited Q GluR2(Q)-containing AMPA receptors are Ca 2+ permeable

  8. Motor system comprised on motor neurons controls muscles in our body

  9. Amyotrophic lateral sclerosis (ALS) /Lou Gehrig disease (motor neuron disease) Neurodegenerative disease with progressive paralysis leading to death in 3-5 years. Selective loss of motor neurons in the ventral horn and motor cortex.

  10. Motor neurons from ALS patients have reduced GluR2 editing Kawahara and Kwak, 2004

  11. TUNEL assay to measure toxicity of AMPA receptor subunits Rat embryonic (E18) hippocampal neurons 14 DIV on coverslips Infect with sindbis virus expressing GluR subunits Treat with glutamate/AMPA/other 17 hours after infection. Incubate for 8 hrs. Fix, TUNEL assay and immuncytochemistry Image on confocal Quantitate

  12. Excitotoxicity in GluR overexpressing neurons GluR2Q GluR2Q+AMPA GluR2- Green TUNEL- Red

  13. A B GluR2(Q) is the most toxic of all AMPA receptor subunits

  14. GluR1 and GluR2/3 follow different trafficking pathways to reach neuron surface. Only GluR2 binds NSF, a trafficking protein.

  15. GluR2(Q) mutant that does not bind NSF does not reach surface efficiently and shows reduced toxicity

  16. N Ligand binding domain Flip/Flop region TM1 TM2 TM3 TM4 NSF binding domain C RNA editing R607Q Inhibitory peptide pep2m

  17. A B

  18. Conclusions: Failure of GluR2 editing at the Q/R site greatly enhances the excitotoxic potential of GluR2. NSF helps maintain surface GluR2 levels hence contributes to unedited GluR2 toxicity. Blocking the interaction of GluR2 and NSF with pep2m reduces the toxicity. Pep2m may be employed as a potential therapeutic reagent.

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