xliii) c. isogenic PHENotype
| Neurodegeneration | Neurite process morphology Network complexity | ||
| Mt | Park2: mt translocation, mitophagy Mt respiration | ||
| synapse | Electrophysiological impairtments Neurotransmitter production, release and uptake | ||
| ROS | |||
| Lysosomal |
xliv) Correlation
| W human postmortem | W rodent | ||
|---|---|---|---|
xlv) Xenograft
a. Method: human iPSC-derived neural progenitors may be trans brains244 planted into animal
| advantage | Cons |
|---|---|
| If the phenotypes observed in vitro are recapitulated in vivo, pharmacological | the healthy host tissue compensate for the impairment of the transplanted cells. Yet, |
GAPFREE3
xlvi) 300 sPD patients (all alive)
a. Clincal data (이 환자들이 다른 takeda 임상참여기 때문에 , takeda는 access없을 수도 있음)
- a. They should have UPDRS,
- b. No imaging data
- b. f/u
- a. period is short yet
- c. iPSc
- a. 150 cases
- d. Genetic testing in 30 cases (?)
- a. 2 GBA cases found
- b. No familial mutation found
Goal
- a. Rapid progressor
- i. 이건 말 안 되잖햐, 이미 우리는 ㄴ아는데
- b. L-dopa responder vs non-responder
- c. Correlation : genetic – antemortem sample (CSF?) – clincial – iPSC
- d. Yuya Kunisada
agree with the importance of transcriptome data for detecting mechanistic phenotype in PD-iPSCs. Detecting disease end phenotypes in iPS-DA (e.g. DA cell death or pSyn accumulation) seems to be challenging, especially for sporadic PD. We might be able to detect mechanistic phenotypes (transcriptome or organelle morphology) in sPD under stress condition and analyze this big data by ML software for patient stratification and biomarker finding. It is what I wanted to do in GAPFREE3. If we can combine the transcriptome data of iPSCs with the data from PD patient brain, it would be great.
i.
SA’s group
Mid-brain organoids with FTD-tau
University of Cambridge
- Established organoid with iPSC
- FTD-MAPT
- Organoid slices sustained in culture
| To do | |||
|---|---|---|---|
| Mid-brain organoids with FTD-tau | University of Cambridge |
- Established organoid with iPSC - FTD-MAPT - Organoid slices sustained in culture |
- Protocol-transfer to TSHO (FY22-23) - Establish relevant assays, e.g. application of tau seeds to induce tau pathology - Determine supporting programs |
Iron
Normal roles of iron
In neuronal metabolism, a component of proteins involved in cellular processes such as DNA synthesis, oxygen transport and mitochondrial respiration. It
For instance, iron serves as a co-factor for the enzyme tyrosine hydroxylase that is involved in synthesis pathway. As such, in vitro studies show that tyrosine hydroxylase activity is dependently by iron (Rausch et al. 1988). The versatility of iron is related to its ability to be an electron donor or acceptor.
Normal distribution of iron
In living organisms, it occurs either in its reduced Fe2+ (ferrous) or oxidised Fe3+ (ferric) state, often in redox equilibrium. In healthy aged SN (dopaminergic neuron 이 아니라는 의미?), many deposits of reactive ferric iron are detected by histochemistry in glia and non-NM neurons (Fig. 3a-c), but reactive ferric iron deposits are undetectable in pigmented SN neurons due to efficient NM sequestration.
iron storage protein: ferritin
lvii) Regional distribution
a. globus pallidus > putamen > substantia nigra > caudate nucleus > cerebral cortex = cerebellum (Dexter et al. 1993).
Normal physiology
| Fe2+) Iron (absorbed from the duodenum binds to transferrin and circulates in the blood | the iron is taken up into the cells via i) transferrin receptors, ii) DCT1 (divalent cation metal transporter;), iii) lactoferrin receptor | where it is stored in the centre of metalloproteins. | Excess iron in mucosal cells is stored as bound to ferritin / neuromelanin (?) |
| (Glial cells do not have transferrine receptors, but uptake iron.) |
Ferritin
lviii) a protein bound to (and store) iron (ie ferritin 은 protein 이지 iron 아님!)
- a. heavy (H) ferritin: mainly in neurons, and oligodendrocytes
- b. light (L) ferritin: on microglia, and oligodendrocytes, in Neuromelanin granules
Pathophysiology
| where the iron concentrations exceed the binding capacities of transferrin. | ↑ cellular uptake of iron, | ↑ unbound or free iron in the cell. | ↑ Fenton reaction and Haber-Weiss reaction (in the presence of iron) : H2O2 is converted to toxic ROS |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| GAPFREE3 list ordering | Roman/letter numerals (xlvi, a, b…) | The mixed roman / latin lettering reflects the source’s ordered-list style; outline depth alternates between styles. |
| GAPFREE3 Korean fragment | 이건 말 안 되잖햐, 이미 우리는 ㄴ아는데 | The trailing ㄴ아는데 looks like a typo for 안다는데 / 안 다는데. |
| Normal physiology row | the iron is taken up into the cells via i) transferrin receptors, ii) DCT1 (divalent cation metal transporter;), iii) lactoferrin receptor | The semicolon inside the parens after transporter is unusual; could read as a comma. |
| GAPFREE3 100/150/30 cases bullets | numeric values | The numerals 300, 150, 30 are clearly readable but the secondary nesting (a/b/c sub-bullet structure) follows Word’s auto-numbering; transcribed as visible. |