Sidransky 2012 review (continued), PD-GD / GBA1-PD notes, GBA gene, GBA Mutation detection method
Sidransky 2012 review table continuation
| source | model | result | note / criticism |
|---|---|---|---|
| Cleeter (2013) continuation | (undifferentiated) 1. SH-SY5Y + CBE 2. SH-SY5Y w/o GBA | 1. ↓ Mito functio 2. ↑ a-syn 3. no change in lysosomal 4. no change in UPS | |
| V Cullen, SP Sardi, J Ng et al. Acid β-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter alpha-syn processing Ann Neurol, 69 (2011), pp. 940-953 | Cell lines MES | ↑ a-syn | thus not supporting loss-of-function theory) |
| PC12 w CBE (10,50,100uM), duration not said | No change | ||
| HEK293 | a-syn altered | ||
| Mouse (a point muta KI) /D409/V/D09V | ↑ a-syn in hippocampus (by both mutation & enz downregulation) that could be reversed by rapamycin, an inducer of macroautophagy | Not in hetero 3. D409V mut is not reported in GD and doesn't manifest typical Gaucher features. 4. The neuropathology in the mice suggest that a-syn is not associated with GBA activity or substrate accumulation | |
| SP Sardi, J Clarke, C Kinnecom et al. CNS expression of glucocerebrosidase corrects alpha-syn pathology and memory in a mouse model of Gaucher-related synopathy Proc Natl Acad Sci USA, 108 (2011), pp. 12101-12106 | Mouse (a point muta KI) /D409/V/D09V | ↑ a-syn in hippocampus | ↓ memory (reversed by GBA) |
| YH Xu, L Jia, B Quinn et al. Global gene expression profile progression in Gaucher disease mouse models BMC Genomics, 12 (2011), p. 20 | Mouse / homozygous for V394L or D409H, which have a normal lifespan and do not show storage of glucosylceramide in the CNS, were crossed with mice deficient in prosaposin, including the peptide saposin C, | ↑ a-syn in cortical neurons (이상하다 이 논문에 a-syn 없는뎅? 2008논문에도 없고) | Model 은 괜찮으나 (정상수명?이라는 점과 기질축적이 없음이라는 단점을 saposin C로 보상했으니) a-syn aggregation was not related to glucosylceramide accumulation 원래 이 모델은 기질 축적이 없는데 saposin 없애서 기질 축적을 유도했음. (원래 saposin은 sphingolipid분해에 역할) |
| Yap | a-syn and GBA bind physically in normal lysosomes and statilize a-syn to prevent degradation |
Accumulation of α-syn was observed in hippocampal neurons in a point mutation knock-in mouse model of Gaucher’s disease with genotype D409V/D409? (Cullen et al. 2011, PMID , Sardi et al. 2011, PMID 21730160). However it should be noted that, although this mouse model shows decreased glucocerebrosidase activity, D409V mutation is not reported in Gaucher’s disease and this animal model does not typically manifest Gaucher features (Sidransky and Lopez 2012, PMID).
PD-GD / GBA1-PD notes
| left label | note |
|---|---|
| PD-GD |
- Concurrence of PD & - GD - Increased incidence of PD in Gaucher carriers, Some GD patients develop PD with alpha-syn positive inclusions - The 2 most common mutation (N370S and L444P is found in PD(2.9%, n=721), DLB (3.5%, n=57, 54 of them were postmortem), control (0.4%) (Mata, 2008 #824) |
| ↑ a-syn → ↓ Glucocerebrosidase (Mazzuli 2011) |
1. ↑ a-syn → ↓ SNARE protein → ↓ ER-Golgi trafficking of glucocerebrosidase → ↓ lysosomal glucocerebrosidase activity 2. ↓ glucocerebrosidase in PD w/o GBA mutation (post-mortem, Mazzulli 2011) |
| GBA mutation → ↑ a-syn aggregation (does this contribute to impaired a-syn clearance?) |
1. In PD If GBA mutation O: glucocerebrosidase present (co-localized) in 75% of Lewy bodies If GBA mutation X: glucocerebrosidase present in 4% of Lewy bodies 2. (Xu 2011) In mice lacking glucocerebrosidase → ↑ a-syn 3. Glucocerebrosidase found in Lewy bodies in GBA heterozygotes (O.Goker-Alpan 2010) |
| GBA mutation --> not always a-syn |
1. PD & a-syn are found in only some GD patients. 2. (Mazzulli 2011, Fig 6) The absence of oligomeric a-syn in samples from type I GD without parkinsonism (Figures 6D and 6E) |
| ↓ glucocerebrosidase → ↑ a-syn (Mazzuli 2011) | Glucocerebosidase KO → ↑ substrate accumulation → ↓ lysosomal degradation pathway → ↑ a-syn level by ↑ polymerization & inhibiting its clearance → ↑ amyloid fibrils → ↑ cell death |
| GBA1 → PD |
(Sidransky 2009) • the most common genetic risk factor for Parkinson's disease that have been identified to date. • Any GBA mutation in non jewish population: OR: 6.51 (7% vs 1.something) • Clinical phenotype: those with a mutation presented on average 4 years earlier, were more likely to have a family history of Parkinson's disease, and had a lower incidence of bradykinesia and resting tremor and a higher incidence of cognitive changes, (Neumann 2009) • In british population OR: 3.7 (4.18 vs 1.17) |
(Suzuki et al. 2018, PMID 29305919)
GBA
GBA gene
- located in a gene-rich region on chromosome 1q21.
(https://scienceofpd.files.wordpress.com/2018/01/gba-variants.jpg) The GBA1 gene and mutations associated with Parkinson’s. Source: Neurology (http://n.neurology.org/content/69/12/1270)
- It is composed of 11 exons and includes around 7000 base pairs of DNA, and 10 introns, spanning 7.6 kb in total and the coding regions of enzymatic active site are located in exon 5-10 (Horowitz et al., 1989) (my thesis).
- Pseudogene (ps GBA1)
- A highly homogenous, untranslated pseudogene that shares 98% homology in the coding regions is located only 16 kb downstream.
GBA Mutation detection method
(Nalls, 2013 #622) 보다는 2018 Pastores (GeneReviews)를 봐라!
| method / source | year | note |
|---|---|---|
| example (Atashrazm, #519) Suppl | 2018 | Cleaned PCR products were sequenced with internal primers, adjacent to coding exons and exon-intron boundaries, using BigDye Terminator v3.1 Cycle Sequencing Kit (ThermoFisher). |
| (Moraitou, #754) | 2011 | patients were tested using PCR and restriction enzyme analysis for eight mutations in the GBA gene that cover approximately 87% of the identified mutations in GD patients diagnosed in Greece |
| targeted mutation test |
- targeted mutation test will identify roughly 89 percent of carriers. - Panel |
- SEMA4
- https://sema4.com/products/test-catalog/expanded-carrier-screen-283/
- 283 GENES
- may be easily customized to address specific clinical needs.
- Turnaround time: 14 days from receipt of specimen
- Gene sequencing can identify over 99 percent of Gaucher disease carriers.
Single gene testing full sequencing of all
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Sidransky table / Cleeter row | ↓ Mito functio | reads as written; the trailing n is clipped from function. |
| Sidransky table / Cullen row | D409/V/D09V; paragraph D409V/D409? | The genotype string is small and split across cells; OCR differs from the paragraph version. |
| Sidransky paragraph | (Cullen et al. 2011, PMID , Sardi et al. 2011, PMID 21730160) and trailing (Sidransky and Lopez 2012, PMID). | The Cullen and Sidransky-Lopez PMID values are blank/not visible in the page evidence. |
| PD-GD / GBA1 → PD row | 7% vs 1.something | reads as written; the writer-side something placeholder is preserved verbatim. |
| Mutation detection bottom | Single gene testing / full sequencing of all | The two trailing lines are clipped; continuation may be in 20240722_182157. |