Neurodegeneration In The Nigrostriatal Dopamine System (DaTscan / VMAT2 PET) And Central Dogma Process (Page 1154)

Neurodegeneration in the nigrostriatal dopamine system — Parkinson’s disease (Takeda slide)

• DaTscan ([123I]β-CIT) SPECT
  • Widely available, used clinically
  • History of use in clinical PD trials
  • Qualified as a patient enrichment biomarker by the EMA
  • Substantial natural history data available (PPMI)
• VMAT2 ([18F]AV-133) PET
  • Higher quality images than DaTscan
  • Preliminary data in PPMI
  • May provide increased sensitivity to DA neuron loss and longitudinal change
  • Takeda is helping to fund PPMI sub-study to expand longitudinal data set
• Longitudinal characteristics of DaTscan SPECT and [18F]AV-133 PET
  • [18F]AV-133 has lower variance across subjects in one year percent change in striatal signal, which translates to a greater statistical effect size and reduced sample sizes to detect an equivalent slowing following treatment
  • The sample sizes shown here are calculated for a 50% slowing of dopamine signal decrease over 12 months
  • These calculations are based on N=345 subjects for DaTscan but only N=17 for [18F]AV-133

clv) John Siebyl on DaT and VMAT2 in PPMI
    a. Early PD imaging markers: AV-133/DaTscan (20210824)

[11C]DTBZ

• Human PET studies have predominantly utilized [11C]DTBZ, (Figure 2) a purposefully designed high affinity metabolite of tetrabenazine, with increasing use in recent years of the molecule [18F] ]fluoropropyl-dihydrotetrabenazine ( AV-133) (Figure 2). (Kilbourn 2021, Biomedicines 2021, 9, 108)

VIVIKI

techniques

	Example
Manual	내가 부평에서 한 것:	structures of interest were outlined manually at baseline and again at f/u
Semiautomated + automated	boundary shift integral (BSI) technique	semi-automated segmentation of the baseline region → automatic calculation of the in
(fully) automated	Voxel-based morphometry

VPS35 (PARK17)

Whole Exome Sequencing

(Bustos, 2020 #2389)	(i) IPDGC5, comprising 1,042 PD cases and 452 controls, (ii) PPMI, with 383 PD cases and 144 controls
(Gaare, 2020 #2390)	(i) The Norwegian WES cohort comprised 191 patients with PD from the Norwegian ParkWest study [10] and 219 controls ii) PPMI) [19]: WES data was available from 640 individuals (459 cases and 181 controls).

References

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[MOLECULAR BIOLOGY]

Central Dogma Process

		location	•
↓	Transcription	Nucleus	DNA → pre-Mrna 시작: A polymerase attaches to promoter of DNA so it can know where to start (핵내) histone 의 methylation → DNA availability for transcription 이 변화됨 (핵내) histone 의 acetylation → ↑transcription gene promoter에서 DNA 가(C나 A) (주로 CpG island 부분에서) methylation되면 → methylated DNA가 MBD라는 protein과 결합 → 다른 protein (histone등) 들도 recruit 되어 → inactive 한 chromatin 되면서 (heterochromatin) → ↓transcription
	RNA splicing (=Alternative splicing, or alternative RNA splicing, or differential splicing)	Nucleus	DNA → Pre-mRNA → mRNA - Definition a form of RNA processing in which a newly made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). - Outcome During splicing, introns (Non-coding regions) are removed and exons (Coding Regions) are joined together - Process For those eukaryotic genes that contain introns, splicing is usually required in order to create an mRNA molecule that can be translated into protein. For many eukaryotic introns, splicing is carried out in a series of reactions which are catalyzed by the spliceosome, a complex of small nuclear ribonucleo proteins (snRNPs). Examples Exon skipping RNA splicing modulators Good review: (Bates et al. 2017, PMID) Strategy : Our compound binds to pre-mRNA itself or RNA-binding agents m RNA leaves the nucleus
	Translation, Synthesis	cytoplasm	Ribosome 이 mRNA로부터 polypeptides 를 synthesize (outside nucleus): → signal recognition particle (SRP) 가 the complex (ribosome, RNA, Polypeptide)를 ER membrane 으로 끌고감 → Protein이 ER 내로 들어감 (translocation)
		ER	Cleaved → protein folding 시작
	Protein folding by chaperones	ER	N-linked glycosylation: The covalent addition of N-linked glycans toproteins is one of the major biosynthetic functions of the ER and disulfide bond formation signal-peptide cleavage glycophosphatidylinositol (GPI)-anchor addition ( occurs in 90% ofall glycoproteins (cf: misfolded protein 은 sugar가 없어 check 당함.)
	Quality control	ER	정상 비정상 Protein에 sugar 가 있는지 check If sugar 있으면 → protein 이 ER 밖으로 빠져나감 → Golgi 가서 (우체국) → final modification (eg glycosylation) → vesicle에 담겨서 target organelle (endosome등)로 이동 If sugar 없으면 → re-glycosylation by the enzyme UGGT (UDP-glucose:glycoprotein glucosyltransferase) 이게 실패하면 ERAD가동 glucose regulate protein 78 (Grp78), a heat shock protein 70kDa family member protein 이 그 protein 에 결합 → 그 protein 을 ER 밖으로 cytosol로 빼서 (chaperone EDEM도움) → UPS 당함 이런 process가 실패해서 protein 이 accumulation 되면UPR 가능: ER membrane에 ER stress sensor가 세개 있는데 (IRE1, PERK, ATF6) 평소엔 ER chaperone BiP (Immunoglobulin heavy chain-binding protein)과 interaction 하면서 inactive 상태로 지냄. → ER에 accumulation된 unfolded protein들이 BiP 에 붙어 그 세 ER stress sensor에서 떼어내면 → UPR가동→ IRE1 undergoes dimerization & phosphorylation→ participates in a cytoplasmic complex→ which splices the transcription factor X-box binding protein 1 (Xbp1).--> Upon its splicing the Xbp1 mRNA (Xbp1s) is translated into a protein that translocates into the nucleus and activates UPR related genes [10–13]. PERK is a kinase that undergoes dimerization and autophosphorylation → ↑ phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) [8]. → Phosphorylated eIF2α attenuates general protein translation in the cells [7,8,12,14,15]. Modified PERK also initiates translation of ATF4→ ↑ transcription of UPR related genes, like the CAAT/Enhancer binding protein (C/EBP) homologous protein (CHOP), which is a proapoptotic bZIP transcription factor [16,17]. ATF6 shuttles to the Golgi, → where it is sequentially cleaved by proteases→cleaved N-terminal cytosolic fragment serves as a transcription factor of UPR upregulated genes [7,11,12,14,19]. ↓단백질 합성, ↓단백질translocation & ↑folding 단백질 transcription 이것마저 안 되면 - Apoptosis (CHOP) or - aggresome 형성 (Retrograde axonal transport시 protein을 끌고가서 MTOC근처에)

DNA replication (DNA → DNA)
DNA Polymerase

Uncertain Spans

location	transcription	uncertainty
References row	repeated 3 characters	The References section is followed by a long band of 3 characters in the source — appears to be a placeholder line with no other text in this capture; reproduced as visible.
VIVIKI techniques table	header VIVIKI	The header reads as VIVIKI in this capture; the V-shaped first letter is small but matches the body_full pixel pattern.
Whole Exome Sequencing row 2	trailing (459 cases and 181 controls).	The right edge of the table is cut at the photo border; the visible numeric cells are reproduced as printed.
RNA splicing diagram cell	example labels GGGGCC repeat / CGG triplet / CCG triplet / GAA triplet / CAG triplet and the ALS / Friedreich ataxia / HD / SBMA / SCA1-3,6,7,17 / DM1 example lists	The example labels accompany the alternative-splicing schematic and read as printed; some are listed under RAN translation disease and translation disease headers.
Quality control 4. row	aggresome 형성 (Retrograde axonal transport시 protein을 끌고가서 MTOC근처에)	The trailing parenthetical Korean note is small and ends close to the photo edge; the reading reproduces the visible characters.