gen scz

Question 1

i. Karunakaran 2019 (Nature)

Answer 1

1. Identified the protein-protein interactions (interactome) of scz associated genes.
2. Looked at which drugs target the interactome and whether they show anticorrelation with the transcriptomic signature seen in the disease (transcriptomics)
3. Identified a shortlist of 12 potential drugs (top 3 were cromoglicic acid, acetazolamide and cinnarizine).
4. No actual screening to see if such drugs alter scz phenotypes – could have done animal model for each repurposed drugs

Question 2

1. Lintunen 2021

Answer 2

longitudinal prospective study showed patients on calcium channel blockers had reduction in scz rehopsitalisation (although concomitant AP was allowed)

Question 3

iv. Yoshimizu et al 2015

Answer 3

used iPSCs to look at functional phenotype associated with an SNP identified in GWAS

1. Generated iPSCs with the allele and without
2. Found higher expression of CACNA1C in those carrying, confirmed by higher VGCC in those carrying by whole cell recording
3. Although iPSCs not same as in vivo

Question 4

v. Yilmaz 2021

Answer 4

1. Overexpressed human C4A in mice
2. IHC and behavioural testing
3. Increased microglial engulfment and reduced synapse density, shown both in the visual system and the PFC
4. In the PFC this was slow and cumulative – maybe this is why scz develops later on
5. These mice also had increased social withdrawal and deficits in working memory
6. Mice without the C4 had normal cortical synapses
7. Maybe C4 could be a therapeutic target?

Question 5

1. Identified the protein-protein interactions (interactome) of scz associated genes.
2. Looked at which drugs target the interactome and whether they show anticorrelation with the transcriptomic signature seen in the disease (transcriptomics)
3. Identified a shortlist of 12 potential drugs (top 3 were cromoglicic acid, acetazolamide and cinnarizine).
4. No actual screening to see if such drugs alter scz phenotypes – could have done animal model for each repurposed drugs

Answer 5

i. Karunakaran 2019 (Nature)

Question 6

longitudinal prospective study showed patients on calcium channel blockers had reduction in scz rehopsitalisation (although concomitant AP was allowed)

Answer 6

1. Lintunen 2021

Question 7

used iPSCs to look at functional phenotype associated with an SNP identified in GWAS

1. Generated iPSCs with the allele and without
2. Found higher expression of CACNA1C in those carrying, confirmed by higher VGCC in those carrying by whole cell recording
3. Although iPSCs not same as in vivo

Answer 7

iv. Yoshimizu et al 2015

Question 8

1. Overexpressed human C4A in mice
2. IHC and behavioural testing
3. Increased microglial engulfment and reduced synapse density, shown both in the visual system and the PFC
4. In the PFC this was slow and cumulative – maybe this is why scz develops later on
5. These mice also had increased social withdrawal and deficits in working memory
6. Mice without the C4 had normal cortical synapses
7. Maybe C4 could be a therapeutic target?

Answer 8

v. Yilmaz 2021