α-Synuclein and Lewy pathology in Parkinson’s disease – Kalia and Kalia
Table 1. Relationships between genetic forms of Parkinson’s disease and Lewy pathology
| gene | protein | protein present within Lewy bodies | Lewy bodies associated with disease |
|---|---|---|---|
| Monogenic Parkinson's disease | |||
| Autosomal dominant | |||
| SNCA | α-Synuclein | + | + |
| LRRK2 | Leucine-rich repeat kinase 2 | + | +/- |
| VPS35 | Vacuolar protein sorting 35 | - | ? |
| EIF4G1 | Eukaryotic translation initiation factor 4γ 1 | +/- | + |
| DNAJC13 | Receptor-mediated endocytosis 8 (REM-8) | +/- | + |
| CHCHD2 | Coiled-coil-helix-coiled-coil helix domain containing 2 | ? | ? |
| Autosomal recessive | |||
| Parkin | Parkin | + | +/- |
| PINK1 | PTEN-induced putative kinase 1 | + | + |
| DJ-1 | DJ-1 | + | ? |
| Other genetic parkinsonism | |||
| Autosomal dominant | |||
| C9ORF72 | Dipeptide repeat proteins | ? | + |
| SCA2 | Ataxin 2 | ? | + |
| SCA3 | Ataxin 3 | ? | ? |
| Autosomal recessive | |||
| ATP13A2 | ATP13A2 | + | - |
| DNAJC6 | Auxilin | ? | ? |
| FBXO7 | F-box protein 7 | + | ? |
| GBA | Glucocerebrosidase | + | + |
| PANK2 | Pantothenate kinase 2 | ? | - |
| PLA2G6 | Phospholipase A2 group VI | + | + |
| SLC18A2 | Vesicular monoamine transporter 2 (VMAT2) | + | ? |
| SPG11 | Spatacsin | + | ? |
| SYNJ1 | Synaptojanin 1 | ? | ? |
| Other | |||
| POLG1 | Polymerase γ 1 | ? | +/- |
| RAB39B | Rab protein 39B | ? | + |
| 22q11.2 microdeletion | ? | ? | +/- |
이들 Mutation 이 coding 하는 protein 이 LB 내에 발견되는가?
o parkinsonism, LRRK2 has been found to localize to Lewy bodies in Parkinson’s disease[31] but not VPS35 [32]. EIF4G1 or DNAJC13 immunoreactivity in Lewy bodies has only been examined in postmortem samples from patients with Parkinson’s disease with corresponding gene mutations; less than 50% of Lewy bodies were found to be immunoreactive for DNAJC13 [33] and most were nonimmunoreactive for EIF4G1 [34]. Among the proteins associated with autosomal recessive parkinsonism, parkin, PINK1, DJ-1 (reviewed in [24]), ATP13A2 [35], and FBXO7 [36] have all been reported to localize to Lewy bodies.
GBA
| PD w GBA mutations 환자 | PD w/o GBA mutations 환자 | |
|---|---|---|
| GBA가 LB내에 있는 확률 | 75% | <10% |
Supplement: Positive vs Negative
Lysosomal function
| context | positive | negative |
|---|---|---|
| in vitro | KO `{Osellame, 2013 #534}` Mixed mid-brain cultures of cortical neurons and astro-cytes) | CBE (Cleeter, SH) |
| KD (Mazzulli) | CBE (Dermen, SH) | |
| KO `{Bae, 2014 #610}` (Fig 5) | CBE (Dermen, PC) | |
| in vivo | `{Rocha, 2015 #1253}` CBE (100mg/kg, 28 d) → ↑ cathepsin D (protein), ↑ LAMP2A, ↑ LC3-II, (P62 only increasing trend) |
a-syn
| context | positive | negative |
|---|---|---|
| in vitro | CBE (Manning-Bog,SH) | CBE (Cullen, PC12) |
| CBE (Cleeter, SH) | CBE (Dermen, SH) | |
| KD (Mazzulli) | CBE (Dermen, PC) | |
| RNAi `({Zurbruegg, 2019 #687}, SH-SY5Y cells` | CBE `{Zurbruegg, 2019 #687}`, SH SY5Y cells and rat primary cortical cultures | |
| `{Henderson, 2020 #1233}` In PFF-treated mice embryonic (hippocampal능) neurons: CBE → ↑ pS129-aSyn (fig3 f,g,l,i) | `{Henderson, 2020 #1233}` In mice embryonic (hippocampal능) neurons: CBE → = pS129-aSyn | |
| in vivo | `(D409Vgba KI mouse, Cullen)` 12month homoz hippocampus에서만 올라가고, 12month homoz brain stem, 12month hetero, 12 week homo에선 안 올라갔음. | |
|
2013 Osellame: ↑ Oligomeric aSyn in KO mouse (K14-Inl/Inl Mice) Homoz (mid brain, Osellame),, monomeric aSyn 은 no change | KO (K14-Inl/Inl) mouse Heteroz (midbrain, Osellame) | |
|
L444P and R463C point mutation mouse(Ginns,) in Striatum (hetero는 안 쓰인 것 같음) | ||
| CBE (Manning-Bog,midbrain) | ||
| CBE (Ginns) in SN & Straitum | ||
| CBE 100mg, 28 d (Rocha) → ↑ proteinase-K resistant a-syn aggregates | ||
| `{Papadopoulos, 2018 #1273}` CBE+A53T mice: ↑ aSyn soluble monomer in midbrain, striatum aSyn oligomer, (but no change in p-aSyn,), see additional details of Asyn different species and different regions. | `{Henderson, 2020 #1233}` In PFF-treated mice: CBE → ① = dopaminergic neuronal loss in SN (fig 5F), ② GCase inhibition does not induce aggregation of a-syn but rather induces mild neuronal spheroids recognized by 81A, which can cross-react with neurofilament ③ 거의, = aSyn spread (to cortex) fig 6B |
Synapse
| context | positive | negative |
|---|---|---|
| in vivo | `{Rocha, 2015 #1253}` CBE (100mg/kg, 28 d) → c1q, SNAP-25, Synaptophysin, synaptoagmin, synapsin, PSD-95 |
총정리 GBA protein & activity POSTMORTEM
Activity: hetero only 에선 kurzawa가 유일. GlcSph Blood: 에서 단독으로 본 것 없잖아!? (2017 Guedes에선 galactosylsph와의 sum), 이거 못 보나 Sato에게 물어보자.
| sample | GBA protein | GBA activity | GlcCer | GlcSph | Cathepsin D protein | Cathepsin D activity | LIMP2 | LAMP2 | LC3 |
|---|---|---|---|---|---|---|---|---|---|
| Brain |
(Li, 2019 #745) In supplement (Gundner et al. 2019, PMID 30236861) (Gegg et al. 2012, PMID 23034917) (Choi et al. 2011, PMID), (Kurzawa-Akanbi, 2012 #577) |
In supplement (Moors, 2019 #644) (Li, 2019 #745) (Gundner et al. 2019, PMID 30236861) (Gegg et al. 2012, PMID 23034917) (Choi et al. 2011, PMID), (Kurzawa-Akanbi, 2012 #577) |
(Gegg et al. 2012, PMID 23034917 but = (Kurzawa-Akanbi, 2012 #577) but = |
In supplement (Moors, 2019 #644) (Kurzawa-Akanbi, 2012 #577) ↓ | (Gegg et al. 2012, PMID 23034917 but = | ||||
| CSF |
Schondorf et al. 2014, PMID 24905578) In supplement (Parnetti et al. 2017, PMID 28843015) |
(Huh, 2021 #2538) PPMI, ↑ (~20%) | Ask Comp Bio | ||||||
| Brain | |||||||||
| CSF |
(Xicoy, 2019 #2540) 2nd, Publication available in sPD |
(Xicoy, 2019 #2540) 2nd, Publication available in sPD |
(Xicoy, 2019 #2540) 2nd, Publication available in sPD |
| PD only | PD+ heteroz | Hetero only | GD only | PD+GD | |
|---|---|---|---|---|---|
| Fibroblast | GlcSph증거없네? |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Lewy pathology continuation paragraph | o parkinsonism, LRRK2 has been found... | The paragraph begins mid-sentence with o parkinsonism,; the leading words are clipped at the top of the section. |
| Positive vs Negative / a-syn / in vivo row | 12month homoz hippocampus에서만 올라가고, 12month homoz brain stem, 12month hetero, 12 week homo에선 안 올라갔음. | Punctuation/spacing in mixed Korean-English text is preserved as visible source. |
| Postmortem matrix | (Choi et al. 2011, PMID), | The PMID number is not visible after PMID; the trailing comma is preserved. |
| Postmortem matrix | column-row alignment for the lower (Brain / CSF) duplicated rows | The matrix has two Brain and two CSF rows; the lower pair appears to be a separate sub-section, but the leftmost label cell is partially clipped. |