GPR37
Target
- Insoluble form of GPR37 has been reported to accumulate in the brains of AR-JP patients [9],
- mice lacking GPR37 are partially protected against dopaminergic cell death caused by 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine [12].
- In SN (other regions?) of sPD (Braak stage 3-6): ↑ GRP37 protein (both overall & N-term cleaved form), ↑ GRP37 mRNA, in sPD
Genetic evidence
Strong
Bm
ecto-GPR37 as a potential PD biomarker
- ↑ amounts of ecto-GPR37 peptides in the CSF samples from PD patients
- PROCess
- To test if BM is to exist in CSF: immunoprecipitation with antibody → identification of the isolated peptides using LC-MS
- Assay development (ELISA, Species-specific) →
- measure in mouse CSF →
- measure in post-mortem human CSF (control & ↑ PD): small cohort →
- measure in post-mortem human CSF (control & ↑ PD): a larger and different cohort
: good ROC, but no correlation with disease severity
- No IVC
- No mechanistic study
Questions
- Target vs bm
- Stratification
- PD-responsible neurodegeneration mechanism
Glossary
| WPRE | WHV's post-transcriptional regulatory element | Salk Institute scientists have identified cis-acting RNA elements from the Woodchuck Hepatitis Virus (WHV) that substantially increase the expression of transgenes delivered by retroviral vectors, in particular WHV's post-transcriptional regulatory element (WPRE). Insertion of specific WPRE in the 3′ untranslated region of coding sequences carried by either oncoretroviral or lentiviral vectors substantially increased levels of gene expression in a transgene-, promoter- and vector-independent manner |
| WHV | Woodchuck Hepatitis Virus |
H&Y (Hoehn and Yahr)
| Stage | Hoehn and Yahr Scale | Modified H and Y Scale | Median Time to Transit (Zhao et al. 2010, PMID 20213822) from previous stage (Months) | Mean duration (accumulated) 2013 Kordower from stage 1 (year) | Median time after stage 1- (Beaulieu-Jones, 2024 #2746) fig1과 suppl table 4,5과 좀 헷갈리게 상이 (아래는 fuppl table 5기준) MGB : | MDS-UPDRS total HBS | MDS-UPDRS Motor (on state)(2013 Kordower?) | Putamen TH | Putamen DAT | SNc DA neuron | a-syn | SV2A | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Presymptomatic phase | 4.7 y (Fearnley, 1991 #1529), 5y (Greffard, 2006 #1531) | at the onset of symptoms there was a 68% cell loss in the lateral ventral tier and a 48% loss in the caudal nigra as a whole. (Fearnley, 1991 #1529) | |||||||||||
| 1 | Unilateral involvement only usually with minimal or no functional disability6.5 (비판: autopsy evidence that PD always affects both sides.) | Unilateral involvement only | 4.5 | 14.4 (2017 Skorvanek) | |||||||||
| 1.5 | mild | - | Unilateral and axial involvement | The mean H&Y score at time of clinical diagnosis was 1.6 (2017 Darweesh). 이 이전에 5-7년간 prodromal phase 임 (2017 Darweesh) | |||||||||
| 2 | Bilateral or midline involvement without impairment of balance | Bilateral involvement without impairment of balance | 20 | 1.7 | 6.5 | 18m | (Simuni, 2018 #198) 32.4 (13.1) | [Simuni, 2018 #198]: 20.9 (8.9) | ↓40% (2013 Kordower) | ↓55% (이후 약간 줌)(2013 Kordower) | ↓50-90% (2013 Kordower) | ||
| 2.5 | - | Mild bilateral disease with recovery on pull test | 62 | 6.8 | 18+57m | 18m | 20m | 23.5 (Simuni 와 안 맞음) | 17.7 (2013 Kordower), 28.8 | ↓50-70% (내 추산, 2013 Kordower) | ↓50% (SPECT, 대략, 1999 Ichise) | ||
| 3 | Moderate | Bilateral disease: mild to moderate disability with impaired postural reflexes; physically independent | Mild to moderate bilateral disease; some postural instability; physically independent, HY3 represents moderate disease (Iwaki et al. 2019, PMID) | 25 | 8.9 | 8.5 | 18+57+29m | 18+57+29m | 20+62+25m | 40.5 | ↓85% (2013 Kordower) | ||
| 4 | Severe | Severely disabling disease; still able to walk or stand unassisted | Severe disability; still able to walk or stand unassisted | 24 | 10.9 | 11.5 | 18+57+29+20m | 20+62+25+24m | 58 | an exponential loss pigmented neurons with 45 % loss in the 1st decade. (Fearnley, 1991 #1529) | |||
| 5 | Confinement to bed or wheelchair unless aided | Wheelchair bound or bedridden unless aided | 26 | 13.1 | 15 | 18+57+29+20+27mm (대략 stage 1 후 12 년후 stage 5 도달) | 20+62+25+24+26m (대략 stage 1 후 13 년후 stage 5 도달) | 72.2 |
ating system has been largely supplanted by the Unified Parkinson’s Disease Rating Scale, which assesses limitation of…
S를 DURATION 으로 보자
(2006 Sato Movement Disorders Vol. 21, No. 9, 2006, pp. 1384–1395)
- 발병은 대개 70세 이전임.
- 병 진행 속도는 개인차가 대단히 크다.
- 그럼에도 불구하고 굳이 평균을 내보자면, 발병부터 3기로 가는데, 평균 10년이 걸림
- 발병부터 4기, 혹은 5기로 가는데는, 평균 16-20년 이상이 걸림 (4,5기까지 가는 환자들이 소수라는 것이 실제적인 의미임)
Mean MDS-UPDRS part I score, Mean MDS-UPDRS part II score, Mean MDS-UPDRS part III score
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
Stage 1 / disability6.5 | the visible cell ends with disability6.5 (비판: autopsy evidence that PD always affects both sides.) and the 6.5 digit cluster reads as written. | low confidence on 6.5 numeric meaning. |
Stage 2.5 / 17.7 (2013 Kordower), 28.8 | the cell groups three duration values together; preserved as written. | low confidence on which column the trailing 8.8 belongs to. |
Stage 5 / 18+57+29+20+27mm vs 20+62+25+24+26m | the leftmost cell ends with mm while the next cell ends with m; preserved verbatim. | low confidence on mm vs m. |
Stage 1.5 / 5-7년간 prodromal phase | reads 이 이전에 5-7년간 prodromal phase 임 (2017 Darweesh); preserved verbatim. | low confidence on 5-7 vs 5~7. |