aSyn spreading tail, ER stress, OS, Inflammation, Motor vs Cognition, Cognition / Dementia
aSyn spreading (continued)
| ↑ lipid accumulation → ↓ autophagy → ↓ degradation of aSyn aggregate that were transferred from cell to cell | |
| (Migdalska-Richards, 2020) | aSyn spreading 4m after intrastriatal injection of aSyn PFF in L444P/+ mice |
| (Casey et al., 2019 #592) | ↑ aSyn spreading in intrastriatal injection of aSyn PFF in D409V KI mice |
| (Bae, 2014 #610) in vitro | zinc-finger nuclease-based method to establish an SV2 cell line, SV2GBA, containing nonsense mutations in both alleles of the GBA1 gene, → greatly reduced total GCase activity, ↑ GlcCer, lysosomal dysfunction → coculture with V1S cell line → ↑ aSyn aggregate spreading |
| (Bae, 2014 #610) in vivo | GBA KO cells (GBA -/- SH-SY5Y) were grafted into the hippocampus of heterozygous transgenic mice (Line 61) → Total aSyn and C term aSyn were reduced in |
| a-syn 무관 |
ER stress
| mechanism | literature / evidence | |
|---|---|---|
| ER stress | GBA mutation → trapped in ER and chronic retention → ER Stress & UPR (unfolded protein response) → ↑ apoptosis | (Maor, 2013 #574) Skin fibroblasts from GD patients and carriers of GBA mutations show increases in a number of markers of the UPR, such as binding immunoglobulin protein (BiP) and CAAT/Enhancer-binding protein homologous protein (CHOP) mRNAs and X-box binding protein 1 (Xbp1) and splicing phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) |
| ER stress | UPR explanation | BiP is an ER chaperone and a regulator of the UPR. CHOP is a transcription factor that mediates ER stress-induced apoptosis. Xbp1 is a potent UPR transcription factor that is spliced by removal of a short intron from its mRNA upon UPR activation. Phosphorylated eIF2α attenuates general protein translation in the cells (Farfel-Becker et al., 2009). |
| ER stress |
(Kurzawa-Akanbi, 2012 #577) POSTMORTEM OF 7 GBA+LBD, 5 GBA heteroz carriers: weird finding, level in (GBA+LBD) = Normal control. What about in GBA point mutation mice? RD DDU (GBA-act_cross-DDU meeting 20201215): | |
| ER Stress | GBA mutant → interation with Parkin → ↓ ups → ↑ ER stress | 2011 Westbroek: Mutant GCase, rather than the wild-type protein, was a sub-strate for parkin-mediated ERAD deg-radation, thereby blocking interactions with other parkin substrates and interfering with their UPS-mediated breakdown, which could lead to ER stress and eventual cell death |
| (right side) null GBA mutations which do not result in a protein product (such as 84GG, IVS2+1, R359X [51], it is possible that the ER stress observed in GBA models with mutations may be due to a-syn accumulation rather than accumulation of GCase itself | ||
OS
| mechanism | literature / evidence | |
|---|---|---|
| OS | ↓ GBA activity → ↑ lipid accumulation → ↓ mitophagy → Mitochondrial dysfunction → ↑ ROS → cell death | (Cleeter, 2013 #533) SH-SY5Y: CBE → ↑ oxidized dihydroethidium (DHE; representing ROS), ↓ Aconitase activity (a measure of free radical mediated damage) |
| OS |
Fig. 3: CBE treatment led to increased free radical production and reduced aconitase activity. (A) As a positive control, paraquat pre-treatment at 300 μM for 1 day (cross-hatched bar; '+PQ') significantly increased the rate of DHE oxidation, as analysed by paired t-tests (p = 0.002). Continuous treatment of SHSY-5Y cells with 50 μM CBE (open bars) showed a progressive increase in the rate of DHE oxidation after 20 days (*p < 0.01, mean percentage changes with respect to the untreated control (solid bar) ±SEM) as determined by one-way ANOVA followed by Dunnett post test. (B) Aconitase activity was significantly reduced (to 37% of control) after 30 days of CBE treatment | |
| OS |
Cf) 2013 Osellame 은 mitochondrial dysfunction 에 의한 ROS 만을 봤음 Cf) oxidative stress levels are generally higher in the striatum and hippocampus (Crivello et al., 2005) and high intrinsic oxidative stress in susceptible neurons has been shown to inactivate PP2A (Foley et al., 2007), which in turn increases a-syn phosphorylation. | |
Inflammation
| mechanism / content | citation | |
|---|---|---|
| Inflammation | ↑ complement → ↑ GlcCer, ↑ inflammation | (Pandey et al. 2017, PMID) |
| ↑ GlcCer → ↑ inflammation | (Gegg, 2018 #580 (2nd) | |
| ↓ autophagy → mitochondrial dysfunction | (Osellame, 2013 #534) This involves: ↓ autophagy → mito-chondrial dysfunction, ROS generation via complex I |
Motor vs Cognition
| site | Mechanism and key biomarkers (red) | POM | ePOC | POC | |
|---|---|---|---|---|---|
| Motor | NS | 원래 aSyn pathology is present (in SN) → ↓ GBA activity → ↑ GlcCer/GlcSph → (Lipid tubule as scaffold) → ↑ aSyn pathologic conversion → ↑ LB in SN (↓ autophagy는 직접적 역할 없음) Early PD Progression: similar to GBA-PD. In the context of aSyn, we try to activate GBA in neurons, so there should be as many neurons as possible. | DATScan | MDS-UPDRS III | |
| Motor | NS | 원래 aSyn pathology is present → ↓ GBA activity → ↑ GlcCer → ↓ lysosomal function → ↑ aSyn spreading within NS → to GP, Thalamocortical pathway | DATScan | MDS-UPDRS III | |
| Cognition | Cortex | 원래 aSyn pathology is present → ↓ GBA activity → ↑ GlcCer → ↓ lysosomal function → ↑ aSyn spreading to cortex 원래 Early PD때는 dementia (moca<21)이 너무 적다 only 3.9% of all PD, (A. Siderowf, 2019 from PPMI) MCI는 15-30% PPMI 2019 Annual Presentation Late PD, ! Cilia | ? | MOCA |
PPMI? 는 EARLY 라 안 차이?
Meta analysis
Most response phase is advanced stage?
| early | Advanced | |
|---|---|---|
| ↓ Cognitition | ||
| neurodegeneration |
Cognition
PD / MCI
| field | content |
|---|---|
| phenotype | PD; MCI |
| progression | y1 14-34% → y5 16-28%: 별로 진행 안 하는 듯 (MoCA declines only about 0.5 points over 5 years) |
| (Zhou, 2020 #623) | 정상cognition 이었던 94명 Early iPD (H&Y 1.7)중 28%가 28m후 MCI 생김 MRI: extensive atrophy in temporal lobe at follow-up (28 m interval) correlation between temporal volume at follow up, frontal lobe at baseline between letter-number sequencing, semantic fluency |
| GBA+PD | 2016 Davis (H&Y 2): GBA carrier n=27, E326K n=31. 38.4%로 두배 많이 (OR=2.18) MCI+Dementia로 진행 |
| (right interpretation) | Early에선 차이가 두 군간 없고, advance로 가면서 차이가 뚜렷해짐. → 후기에서 GBA가 mechanism적으로 역할 하는구나, 라고 생각 가능함. Iwaki 자료 고려 |
Dementia
| field | content |
|---|---|
| phenotype | Dementia |
| progression | Year 1 0.7% → y5 3.6% |
| (Buter, 2008 #627) | At baseline, (27%) had dementia (DSM, mmse 등) |
| 2019 Siderowf | 두 군 사이에 MOCA 점수가 no difference! (82 GBA+PD patients) |
| (Cilia, 2016 #163) | n=2764 total, 123 GBA carriers - 67 mild (p.N370S) and 56 severe (mainly p.L444P) disease durations were 12 y, (but H&Y stage 3기이상 비율이 38%), mild to moderate라고 봐야겠군. Unadjusted cumulative incidence for dementia using Kaplan-Meier methods Dementia (DSM-IV) was 19.6% vs 34.1% (아마 at baseline) |
Cilia 2016 Kaplan-Meier dementia figure labels:
A. KM for dementia on disease duration - scale
- Series: Non-carriers, GBA-carriers, GBA-MM, GBA-SM
- y-axis: Cumulative incidence
- x-axis: Disease duration (yrs)
- Log-rank test: Non-carriers vs GBA-carriers <0.001; GBA-SM vs GBA-MM =0.027
GBA-PD / Phenotypes (assays) / Models / Status / Current/future plan (start)
| GBA-PD | Phenotypes (assays) | Models | Status | Current/future plan |
|---|---|---|---|---|
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Bottom GBA-PD table | most cells blank or clipped | the lower table starts at the bottom of the photo with column headers only; cell contents are blank or clipped. |