MOA of aSyn spreading tail, Antibodies to aSyn (matrix + per-antibody host/Species/epitope), Vaikath 2019 #1599 antibody fragment map, Astrocytic aSyn (Aflaki 2020 GD1/GD2 iAstrocytes), CSF & Blood Total aSyn level start
Antibodies to aSyn
| Pathologic conversion | Pathological aggregation | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| monomeric | tetramer | Phosphorylated a-syn | Misfolded monomer | B-pleated sheet | insoluble | Oligomeric (still soluble) ((Wang et al., 2016)) | protofibril | (insoluble amyloid-like) fibril | Lewy bodies | Total a-syn | |
| Antibody | (20200414) ADx Neurosciences, TV Q3 FY2020, CS : Q42020, • 기존 : anti-pS129 a-syn polyclonal antibody (Santa Cruz) | (Waxman, 2008 #535) Syn505, Syn506 and Syn514 recognize conformational variants of α-syn | Thioflavin-s staining (antibody는 아니지만) |
• (20200414) ADx Neurosciences, TV Q4 FY2020, CS : Q3 FY2021, A-mouse anti-α-syn fibrils/oligomers (O2; [43]), |
mouse anti-α-syn fibrils/oligomers (O2; [43]) mouse anti α-syn fibrils (F2; [43]) | ||||||
| -current Abs can't distinguish physiological (HC) between pathological species (PD pts) | |||||||||||
Per-antibody host / Species / epitope
| Antibody | host | Species | epitope | note |
|---|---|---|---|---|
| A11, AB9234, Merck Millipore | antibodies specifically raised against oligomeric forms of a-syn but bind to Aβ as well | |||
| OC, AB2286, Merck Millipore | anti-amyloid fibril antibody (Aβ as well) | |||
| SNL1 | Murine and human, but (Yazawa, 2005 #1440) only mouse aSyn) | PNAS. 2009. 106: 20051 SNL1 and SNL4: pan aSyn antibodies | ||
| SNL4 | PNAS. 2009. 106: 20051 SNL1 and SNL4: pan aSyn antibodies | |||
| LB509 | specific for human | 115-122 | ||
| C20 | human, mice, rat (alzforum), | Cterm of aSyn | ||
| 81A | human | Only phosphorylated aSyn | ||
| Syn-1 | human | 91-99 | ||
| Syn03 | ||||
| Syn 202 | aa 130-140 (Giasson, 1999 #2823) | Human aSyn (aSyn propagation suppressor slide) | ||
| Syn204 | specific for human | Aa 87-110 (Giasson, 1999 #2823) shares aa 87-109 | ||
| Syn 205 | aa 130-140 (Giasson, 1999 #2823) | |||
| Syn 208 | Aa 87-110 (Giasson, 1999 #2823) | |||
| Syn211 | Only human, | 121-125 | PNAS. 2009. 106: 20051 Syn506 and Syn211 mostly recognized α-syn antibodies | |
| Syn303 | ||||
| Syn506 | BD Biosciences | only recognized aa residues 125-129 of α-syn (non-p form) | Used in NURR's Atuka study | |
| EP1536Y (=ab51253) | HUMAN & mouse & rat | |||
| 610787 (BD Biosciences) | Pan aSyn | |||
| Syn1150 | only recognized aa residues 125-129 of α-syn (non-p form) | |||
| D37A6 | Only mouse | |||
| MJFR1 | Only human | |||
| Syn-O2 | Majbour 2016: specifically recognizes early soluble "oligomers" and late aggregates "amyloid fibrils" of α-syn (Fig. 1a), and has a high binding affinity for o-α-syn species (apparent KD value of ~5×10⁻¹¹ M) [24]. It exclusively detects o-α-syn aggregates (amyloid fibrils and soluble oligomers) without cross-reactivity with monomers or fibrils in conjunction with Nells but Otake- Five years ago I have tried to detect RT QuIC reaction product in western blotting using one of Du I could not any signal | |||
| MJFR-14-6-4-2 | (Vaxxinnity AD/PD 2024 update) | |||
| 2A1 | (Majbour 2021) a conformation specific antibody that specifically recognizes α-syn aggregates both full-length (1-140 aa) and C-terminally truncated (1-1...) | |||
| 3G7 | (Majbour 2021) 3G7, a conformation specific antibody, recognizes a wide range of α-syn forms including C-terminal truncated forms (Fig. S2; ?) | |||
| 4D6 | Full length aSyn, cross-reactive with paSyn | |||
| 5C2 | mouse | 61-90 | ||
| 5G4): | 5G4 specifically recognizes aa 47-52 in B-sheet form of α-syn oligomers, do not capture normal oligomeric αSyn | |||
| x122 a-syn antibody | (A15127A from BioLegend) | on the a-syn (1-121) https://www.biolegend.com/ja-jp/products/purified-anti-alpha-syn-c-terminal-truncated-a-122-13986?GroupID=BLG11651 may recognize neo-epitope which is not exist in full length a-syn (but a little bit skeptical) |
(Vaikath, 2019 #1599) list and summary of antibodies with (conformation-specificity) in table 1
A: aSyn fragment map labels visible: A30P, A53T, NAC, Pan-Syn (1-95 region highlighted), N-1&2 (1-61), NAC-1&2 (61-95), Syn-1, Hu-Syn (95-140), NACP-C, 140
above Li, 2005 #2044
Astrocytic aSyn
Astrocytic inclusions of αSyn are invariant features in PD and DLB but observed less frequently in MSA (Sorrotion, 2019 #1138).
mechanism (when astrocyte don’t express asyn)
- {Aflaki, 2020 #1141} in Gaucher iPS-derived astrocytes,
- ↓ glucerebrosidase activity (GD1 iAstrocytes showed the expected reduction in GCase activity (~35% of control), whereas GD2 iAstrocytes had severely deficient (<5% of control) GCase activity (Fig. 2C)
- accumulate glucoslyceramide, upregulated GFAP and several astrocyte astrogliosis
- iAstrocytes from the subjects with GD1 with a parkinsonian phenotype
- two lines generated from the subject with GD2 had 3.5 and 5.6 fold elevations in GlcCer than control iAstrocytes. Cells from two lines generated from the subject with GD2 had 3.5 and 5.6 fold elevations in GlcCer level compared to those from an infant control (Fig. 2G).
- GlcSph levels were significantly elevated in GD2 iAstrocytes (10-20 fold) (Fig. 2E)
- Excessive α-syn from neurons is taken up by astrocytes and moved into lysosomes (iDA neurons 과 co culture 실험 통해서)
- Cathepsin D activity is low in iAstrocytes from Parkinson’s disease and GD2 patients
CSF & Blood (a-syn)
[Total aSyn level]
- Hansson 2014, Skåne University Hospital, Sweden: 60 ng/L, ↓8% (a new)
- Majbour 2021: DenoPa 826 pg/Ml, ↓8%, in-house
- Majbour 2016, VUMC, : 1.5 ng/mL, ↓19% (p<0.05), in-house
- van Steenoven, 2018, VUMC, 1.5 ng/mL, ↓22%, the same assay as M
- {Schirinzi, 2019 #615}, Italy, 1,000 pg/mL, ↓33% p<0.05, ELISA kits (Covance=BioLegend), ~1.5 ng
- {Baek, 2021 #2734} ppmi, ELISA kits (Covance=BioLegend), ~1.5 ng