Vanishing White Matter

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spasticity

Back 1

progressive gait difficulties

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European descent

Back 2

What can be said about most VWM patients' history?

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wide spectrum

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Rapid death to slow neurological progression

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chronic progressive

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course of VWM

Front 5

Liu et al (2011)

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No!

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Y495C

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this mutation does not affect GEF activity or holoenzyme complex formation

Front 7

Labauge (2009)

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multiple groups have reported cases with no actual vanishing of the white matter

Front 8

Fogli & Boespflug-Tanguy (2006)

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did not find a hot spot; also when eIF2B activity is comparatively low, some genes such as ATF4 are upregulated

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43S initiation complex

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what is eIF2 a part of?

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40S

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what is eIF2 bound to?

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after factors have left

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whan does the 60S join?

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each round of initiation

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how often is eIF2B required?

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3q27

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where was the 5cM region

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haplotype EN

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They reduced the 5cM region to 2cM region thanks to what?

Front 15

Leegwater et al (2001)

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Who did the breakthrough?

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PERK

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What phosphorylates eIF2?

Front 17

other translation initiation factors only get activated in even higher temperatures

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Why is eIF2B the only mechanism for fever response?

Front 18

ATF4

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what get upregulated, contrary to everything?

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V409L

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CACH mutation

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R195H

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Cree mutation

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R113H

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common mutation

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30%

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although ~70% of mutations involve epsilon, what portion of the holoenzyme does it consitute?

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fever-indiced liver or bone marrow failure in infants

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'viral infections'

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van der Knaap et al (2003)

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this group found defects in eyes, kidney, spleen, and pancreas of 9 VWM patients

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not another-yet undected pathogenic mutation

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R113H's independed occurence proves that

Front 26

Fogli et al (2004)

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They were wrong because of limited number of mutation studies

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long processes and flat end feet

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abnormal astrocyte morphology

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mixed lineage phenotype

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astrocyte weird marker phenotype

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GalC

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oligodendrocyte marker

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GFAP

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astrocyte marker

Front 31

Dietrich et al (2005)

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astrocyte study

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R132H, R136H

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human mutation that was replicated in the mouse model and the equivalent mouse mutation

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iPSCs with genetic modifications

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the best therapy idea

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cuprizone

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model for experimental demyelination and remyelination

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Geva et al (2010)

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mouse paper

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Thapsigargin

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blocks ER Ca pump SERCA

Front 37

Huyghe et al (2012)

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splicing paper

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hnRNPH1 hnRNPF

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were found in nucleus of foetal cells in VWM (controls: in cytoplasm)

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Pelizaeus-Merzbacher disease (PMD)

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disruption of PLP1/DM20 ratio has been implicated in

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DIAPH3

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human equivalent of Diaphonous drosophila gene

Front 41

Labauge et al (2005)

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case study: other genes in the eIF2 stress regulation cascade

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Proud (2005)

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two uORFs ATF4 paper

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stray

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what happens with ribosome (at APF4 mRNA) if eIF2 depleted?