ATP13A2 (Park9) MUA + Animal model + ATSURO MICRO + PXEAEAU Lysosomal protein degradation + SAL BAC + MPO score + Disruption of BBB + BBB disruption in PD + BBB opener Cordance + non-confidential CDA + BD/Process/BeyondBio + Biobank + PPMI
ATP13A2 (Park9) — MUA
| Mutations in ATP13A2 | effect |
|---|---|
| ↓ protein expression through ↑ phosphorylation of MTORG (Zhang, 2021) | ↓ lysosomal acidification (Zhang, 2021) ↑ αsyn accumulation (Zhang, 2021) |
| ↓ autophagosome-lysosome fusion | (normally, ATP13A2 enhances the fusion of autophagosomes and lysosomes by recruiting HDAC6 (histone deacetylase 6), resulting in the deacetylation of CTTN (cortactin), and assembly of the F-actin network (Figure 8A)) |
More recent work has linked ATP13A2 to mitochondrial quality control (Grunewald et al., 2012) and the neuro-protection against metal-induced toxicity (Kong et al., 2014).
Animal model
late 2021: ATP13A2 knockout mice exhibit a neuronal ceroid lipofuscinosis-like phenotype, accumulation of mitochondrial ATP synthase subunit C (132). Specifically, ATP13A2 deficiency causes dysfunctions in the fusion of autophagy vacuoles with lysosomes as well as the impaired turnover of several lysosomal degradation of proteins including α-syn (133).
ATSURO MICRO
Cognition in NWP, object discrimination reversal task data using a modified Wisconsin General Testing Apparatus (ODR-WGTA).
BUCITAL DIO
사실 인 동 정 군구.
PXEAEAU — Lysosomal protein degradation
| content | |
|---|---|
| Cell transferred from PHRet | Budget |
| Pulse-chase, supernatant | Module Human Hi: Lysosomal proteolysis (1) kinetics?) (2) → human cell 사 게이 빅 |
| αSyn degradation |
SAL (Bacterial artificial chromosome)
- Allows larger transgene (~100 kb)
- Review (Heinrich, 2001 #1459)
MPO (Multiparameter Optimization) score
- The algorithm uses a weighted scoring function assessing 6 key physicochemical properties (clogP, clogD, MW, TPSA, HBD, and pKa) for BBB penetration. CYP-mediated metabolism and inhibition of 5-felide bridges.
- The CNS MPO score is between 0 and 6.0 with scores ≥4.0 widely used as a cut-off to select compounds for hit finding in CNS therapeutic area drug discovery programs.
- A recent article assessing 616 compounds with measured unbound concentrations in the brain confirmed increasing CNS MPO score correlates with increased unbound concentration in the brain.
Disruption of BBB
Assay
| example | Protocol | |
|---|---|---|
| Fluorescence isothiocyanate-labeled dextran (FITC-dextran) of average molecular weight 3 kDa, Sigma-Aldrich and rhodamine-labeled dextran (Rh-dextran, average molecular weight 2,000 kDa, Sigma-Aldrich) were used as a gold standard for the evaluation of BBB permeability and disruption. | (Yue, 2018 #2598) tracers were intravenously injected with mixture of FITC dextran and Rh-dextran in the rat vein, which circulated for 1h. After 1h, the rats were anaesthetized and their brains were quickly removed. Localization of Dextran (FITC-dextran [green dot]) and (Rh-dextran [red dot]) was assessed by confocal microscopy; CD33 (red color) and Hoechst 33342 was used as a counter marker. | (Natarajan, 2017 #2210) Results: Supplementary Figure 2D,E (relative extravasation of each) |
BBB disruption in PD
- Living patients (Kortekaas, 2005 #2331) We used positron emission tomography to measure brain uptake of [11C]-verapamil which is normally extruded from the brain by P-gp. Here, we show significantly elevated uptake of [11C]-verapamil (18%) in the midbrain of PD patients relative to controls.
- Postmortem PD (Brochard, 2009 #2332) CD8+ and CD4+ T cells but not B cells had invaded the brain
- MPTP mouse (Brochard, 2009 #2332) CD8+ and CD4+ T cells but not B cells had invaded the brain
- Correction MPTP mouse (Brochard, 2009 #2332) the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (Rag1-/- and Tcrb-/- mice) prevents ↓ DA cell death
BBB opener
process / BeyondBio
- Non-confidential
- If we cannot judge by ourselves, we try to identify those who may have interest in them based on our internal activities, including scientific meeting with the partner at non-confidential base. Then we forward the information to identified persons by asking if they have interests in the opportunities. Or Decline.
- conflict check
- with after confirmation no conflict, we will ask our internal liaison Manager-san to conclude CDA.
BD pipeline (small block)
| 107 | CDK1/Cyclin B inhibitors | Pancreatic ca, Glioblastoma | P1 | P1 in Korea (NJU/H) Hu NCT04476303 | CDK1/Cyclin B inhibitors | |
|---|---|---|---|---|---|---|
| See competitor (CycSecH’s CDK inhibitor diosulane CDK inhibitor) | AD | PRECLINICAL |
Biobank
| bank | Brain sPD | Brain Park2-PD | CSF | BLOOD | Examp | Connect |
|---|---|---|---|---|---|---|
| 1) cells (PHru), 1) cells (inhibitor), 1) iPSC | (WGC underway for 102 PD) | x |
(Biospecimen/Vollstedt 2019 #822: the table GBA = 57; Cf table genetic cohort: J/9 strange 14 vs 4 idiopathic PD form Chahine 2020)
PPMI
| content | |
|---|---|
| ppmi.info.org | Control = 254 PD = 879 SWEDD = 81 Prodromal = 685 = 3 = 2 AV133 = 19 |
| To date, PPMI has enrolled more than 1,000 participants at 33 sites in 11 countries, and enrollment is ongoing. Subjects will be followed up to five years. There are six study arms, and inclusion in each arm is based on diagnosis: - Idiopathic PD - including any PD subjects with no known genetic risk factors for PD - Healthy controls - neurologically normal individuals with no known genetic risk factors for PD |