Qs: why four? Why not lysosome? Gandhi? Klenerman Four disease subtypes of Parkinson’s using patient-derived stem cell models
20230906: Yale, contract, CDA, subtyping papers
| 이재경 |
Imaging capability O, serial sampling x, human samples from Columbia university (on-site x), Calvin Lee from Virginia Lee lab. Giasson at univ of Florida completed removed endotoxin, Endotoxin and aSyn have similar size and neg charge. Removal method: high cathion chromatography and pH optimization, Creiteria? FDA requirement for toxicology? And no TLR4 activation, network with univ of Florida and UAB. RAT model experimece X, but CSF collection from rat was 15-30 uL | ||
| Kimitoshi Nakamura's research while affiliated with Kumamoto University | LSD | ||
| 채종희 |
개인방직봉 02-2072-3622, 비서실 02-2072-3570 [email protected] Department of Pediatrics, Seoul National University, College of Medicine, Seoul, Korea 110-744 | ||
| Anthony Schapira | MD |
-mail: [email protected] Department of Clinical Neuroscience, Institute of Neurology, UCL, Rowland Hill Street, London NW3 2PF, UK Fax: +44 20 7472 6829 Tel: +44 20 7830 2012, 020 3448 3015 | |
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- Sarah Salvage: olimpyic, covid, me GB PD, Alisdair McNeill, Anthony schapira, CSF
Minee Choi
| Subtype | mechanism | stressor | |
|---|---|---|---|
| 1 | SNCAX3 mutation | ||
| 2 | Human recombinant aSyn oligomer | ↑ p-aSyn | |
| 3 | MC1-induced mito dysfunction | Rotenone (↓ mitophagy?) | ↑ # of mito-lyso contact spot, ↑ spot to region intensity. |
| 4 | Mitophagy-induced mito dysfunction | Oligomycin and antimycin |
- ~40 Classifiers to predict five classes four disease subtypes and one healthy state — using tabular data based on the nucleus, mitochondria and lysosome features extracted from imaging
- regarding three key organelles, nucleus (Hoechst3337), mitochondria (TMRM) and lysosome (Lyso)
- dense neural network
- overall, the correct label was identified 82% of the time in the five-class model
- SNCA ×3 = 84%, oligomer = 82%, mitophagy = 81%), (complex 1 = 98%), (control = 69%;
- subtype 1 (SNCA ×3), five were lysosomal, three were mitochondrial and two were nuclear (Fig. 3e);
- subtype 2 (oligomer), seven were mitochondrial, two were nuclear and one was lysosomal (Fig. 3f);
- subtype 3 (complex 1), seven were mitochondrial, two were lysosomal and one was nuclear (Fig. 3g);
- subtype 4 (mitophagy), six were mitochondrial, two were nuclear and two were lysosomal (Fig. 3h).
- Convolutional neural network
Kv1.3
A voltage-gated potassium channel
Expression
- T cells (15, 16) but has since also been identified in B lymphocytes and macrophages, retinal ganglion cells, microglia, and neurons,
STRUCture
- (Like the other 40 voltage-gated potassium channels found in humans,) Kv1.3 consists of 4 α subunits, each with 6 transmembrane segments (S1-S6) and a voltage sensor in the S4 segment that is responsible for opening the channel in response to membrane depolarization
In PD
| Aggregated aSyn | Kv1.3 upregulated & ↑ activity | Neuroinflammation | Neurodegeneration | ||
|---|---|---|---|---|---|
| Evidence | In vitro | In primary microglial cultures: ↑ Kv1.3 ({Sarkar, 2020 #1618}) | |||
| Human postmortem | ↑ Kv1.3 (frontal cortex) ({Sarkar, 2020 #1618}) | ||||
| Animal models | ↑ Kv1.3 ({Sarkar, 2020 #1618}) | ({Sarkar, 2020 #1618}, in multiple animal models) | |||
| correction | ({Sarkar, 2020 #1618}, in multiple animal models) (Kv1.3-specific small-molecule) inhibitor PAP-1 → ↓ neuroinflammation | ↓ neurodegeneration |
Pipeline [Muna Tx]
| Compound | Company | Modality | Route of Admin. | Indications | Product Stage |
|---|---|---|---|---|---|
| azatide | Kv1.3 Therapeutics | Synthetic Peptide | Opthalmic, SC, Topical | Inclusion Body Myositis / MS Plaque Psoriasis / Anterior Uveitis | Phase I |
| Small Molecule Kv1.3 Blocker | Metrion Biosciences | Small Molecule | Oral | Psoriasis, Neurodegenerative Diseases | Preclinical |
| 44 (peptide) | selectION | Synthetic Peptide | IV, SC | Cutaneous T-Cell Lymphoma Arthritis | Preclinical |
| Small Molecule Kv1.3 Blocker | 4-SC | Small Molecule | Oral | Autoimmune Disorders / Rheumatoid Arthritis / MS | Preclinical |
Kyoko Yoshikawa
PD disease area TML,
NDU: BD input
BD → NSTM
- bd활동아는 것이 PD priority, direction 정하는 데에 도움이 된다.
NSTM →
- 너희 bd assessment 시 translational input 필요지 않은가?
- In license 후에 우리가 개발할 때 결국 translational strategy 필요하지 않은가?
- Eg 어느 회사가 MC1 를 INVOlve 할 수 있지 않은가?
- 우리 선략이 mito 에서 Parkin PD → Spd 로의 expansion 선략인데, 그 회사가 여기 부합하는가?
AMBER
SP Letter (202102) Confidential review of an asset to revitalize mitochondria for Parkinson’s disease; Kyoko (with ARNU & PhRET)
BD의 Priority 는 무엇? PD? 에서 어떤 Direction?
R&R in your group
- When I identify external PD opportunity, shall I refer to you (OR Shimojo-san)?
Lee Jonghun
| Correlation 안 중요 (sPD에서 stratification 목적으로는) |
Spd: gene-RNA-Protein/mito BM - UPDRS 4. Identify patients with mito dysfunction 5. 이 군에서 가장 중요한 BM 은 무엇인가? 6. (이 군에서) 이 bm 이 Tx response 있나? |
| Flow | RNA로 어떻게 실제 하나? 환자들 RNA-Seq해서? 여러 gene expression 의 뭉치인데? |
| stratification |
DNA RNA: SN에서의 NEURON에서의 single cell transcriptome 필요. (Only Daria?) Protein |
|
NDE 밀고, DNA/RNA 무용함을 밀자 Amp-pd data의 작음을 질문 Why SNP Validation by protein MJF 에 PARKIN-PD 있나? DARIA on NLRP3 |
Lipid category (eight, by Lipid MAPS consortium)
| category | Synonym | Examples | Function | In PD |
|---|---|---|---|---|
| Fatty acyl | (fatty acid) | eicosanoids, derived primarily from arachidonic acid and eicosapentaenoic acid, that include prostaglandins, leukotrienes, and thromboxanes. Docosahexaenoic acid | ||
| Glycerolipid | triglycerides | |||
| Glycerophospholipid | phospholipid | phosphatidylcholine (also known as PC, GPCho or lecithin), phosphatidylethanolamine (PE or GPEtn) and phosphatidylserine | Lipid bilayer of cells | Good summary table in … |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| 채종희 contact | 개인방직봉 | Korean office-name 개인방직봉 reads oddly; may be a stylized contact label such as 개인 직통; preserved verbatim. |
| Kyoko Yoshikawa bullet | bd활동아는 것이 | Korean phrase bd활동아는 may be bd활동을 아는; preserved verbatim. |