cGAS / cGAMP / AGS

This topic page reorganises the 2 source notes filed under cgas-cgamp into reading-order axes. It does not replace the by-photo Markdown; every claim links back to a source note or the canonical transcription. Where a source carries Uncertain Spans, that uncertainty is preserved here rather than smoothed out.

Overview

The corpus’s cGAS / cGAMP chapter is a tight 2-page early-document cluster that introduces the cytosolic-DNA-sensor → second-messenger → type-I-IFN axis and its PD-relevant readouts. Two overlapping axes organise the 2 sources, one source per axis: (1) cGAS — Senescence and the cGAS-STING Pathway with the Paraquat / iPSC Correction rows, the Sliter 2018 #699 EE-induced PARKIN-/- / Pink1-/- / Prkn-/-; STING… / Pink1-/-; STING… mouse-cytokine and mtDNA-release table, the Biomarker / Readout questions block, the embedded cGAS-STING Pathway figure, the mito damage + senescence matrix, the Executive summary cGAS SharePoint pointer, and the Senescence Basic Hypothesis / Evidence in PD / In Vitro Paraquat / Mouse Model / MOA Integrated narrative (20240722_181843); (2) cGAMP — Assay Development & Monthly Update with the Partial Preceding cGAS Row table fragment, the cGAS-function and cGAMP-isoform primer, the wide DMPK (Iwasaki Shinji, LC/MS) vs NSTM (MSD) monthly-update matrix from 202002 through 202103, the LOD / LLOQ definition box, the STING / RIG-I primer, the cGAS Inhibitor / Pathway Notes baricitinib / RU.521 row pair, and the AGS Transition stub heading whose body continues onto the parkin-side _181851 page (20240722_181847).

The AGS (Aicardi-Goutieres Syndrome) / cGAS transition chapter (_181851 — AGS/ALS/cGAS to Parkin/PRKN Transition, AGS/cGAS Evidence Table Continuation, ALS with cGAS, Rationale, Mechanism) is filed under parkin by its AGS … / cGAS transition > Parkin > PARK2 Gene (=PRKN) nav root and narrated on parkin; this topic cross-links it rather than re-narrating. No new entity page is created in this pass.

Source Boundary / Delegation

This topic is bounded inside sections/cgas-cgamp and includes exactly the 2 sources listed in cgas-cgamp. Adjacent material that overlaps in content but is owned elsewhere:

boundary	adjacent material	owned by
_181851 AGS / cGAS transition > Parkin > PARK2 Gene (=PRKN) — AGS/ALS/cGAS-to-Parkin transition table, ALS-with-cGAS rationale, Parkin-side Mechanism narrative; the AGS Transition stub heading on _181847 opens this chapter	_181851 is filed under sections/parkin by its AGS … / cGAS transition > Parkin > PARK2 Gene (=PRKN) nav root; this topic cross-links rather than re-narrates	parkin / parkin
_181839 TAK-071 > Mechanism page that the _181843 related_photos records as continues_upper_cgas_senescence_evidence (capture-order neighbour, separate program nav root)	TAK-071 cholinergic / muscarinic M1 PAM program rather than cGAS biology proper	gba-pd-asyn · therapeutic-programs § Entity Backlog Candidates (TAK-071)
Sliter 2018 #699 EE-induced PARKIN-/- / Pink1-/- / Prkn-/-;STING / Pink1-/-;STING genotype matrix; serum mito-DNA / cGAMP / cytokine deltas; the Mt-keima / pS65-ub columns; Parkin-deficient mutator mice rescue note; PARK2 KO iPSC-DAn Correction rows on _181843	Parkin / PINK1 mitophagy / pS65-Ub / mtDNA-release biology	parkin / parkn-gt / mitochondria
Mitochondrial damage → mtDNA release → cGAS-STING arrows in the mito damage + senescence table; (cf: there have bee[n] (Fukushima, 2002 #1018) no reports on mitochondrial DNA damage by paraquat) aside; mtDNA release as PD-relevant readout	mtDNA / mitophagy / oxidative-stress disease-side biology	mitochondria
Type I IFN / SASP / MMP-3 / IL-6 / IL-1α / IL-8 / p16INK4a / lamin B1 senescence-marker biology and the Chinta 2018 #936 paraquat → senescent-astrocyte → ↓ DAergic-neuronal-viability conditioned-medium experiments on _181843; cytokine candidates Type I interferon? / TNF-a and IL-12	inflammation / cytokine / microglia-biology disease-side narrative	inflammation / nlrp3-inhibitor
[BIOMARKER] / Biomarker / Readout questions on _181843 (cGAS protein LCMS, ISG selection caveat, cGAS PET diurnal-activation caveat, Type I IFN / cytokine candidate selection); MSD vs LC/MS assay performance criteria (LLoQ < 10 pg/mL, 7.22 nM CSF-cGAMP HV value, individual vs pooled CSF, PrecisionMed sourcing); patient-stratification options (sPD / Parkin-PD / PINK1-PD) on _181847	[BIOMARKER] validation framework, plasma-vs-blood / serum / CSF analyte selection, MJFF Phases of Assay Development	biomarkers-outcomes
LC/MS bioanalytical method development, MSD immunoassay specificity, 2’2’- vs 2’3’- vs 3’3’-cGAMP isoform discrimination, surrogate-matrix / mobile-phase / extraction-method optimisation on _181847; cGAS protein expression LCMS-feasibility note (Niigata univ collaboration 20210129) on _181843	Bioanalytical / molecular-biology / proteomics methodology	molecular-biology
LysoTracker / DQ-Red BSA / autophagy-marker assay vocabulary that the cGAS-STING ↑ ROS release / mitophagy bullets imply; lysosomal-membrane / BMP biomarker biology that frames the cGAMP ELISA-vs-MSD assay landscape	lysosome / autophagy biology	lysosome-autophagy
cGAS Inhibitor / Pathway Notes baricitinib (Olumiant, JAK1/JAK2-STAT) and {Chin, 2019 #765} RU.521 active-site cGAS inhibitor (↓ type I IFNs; no effect on human cGAS) on _181847; Our compound binds activated Cgas, non-activated cGAS에도 붙는지는 확인중 Executive-summary bullet on _181843	cGAS-inhibitor program-routing entries; not promoted to entity pages in v1	therapeutic-programs § Entity Backlog Candidates (cGAS inhibitor PJ)

Neither _181851 nor _181839 is included in the Source Table below. No new entity page is created in this pass; the cGAS-inhibitor program rows remain Entity Backlog Candidates per therapeutic-programs.

Source Coverage

2 source notes are assigned to the cgas-cgamp section, one per first-level nav_path cluster:

nav root (first nav_path entry)	sources	covered axis
cGAS (cyclic GMP-AMP synthase, cGAMP synthase, =mb21d1)	1	cGAS — Senescence and the cGAS-STING Pathway
cGAMP (cyclic GMP-AMP)	1	cGAMP — Assay Development & Monthly Update

For exact nav_path strings and headings see cgas-cgamp and the by-nav indexes listed in related_topics_by_nav. The cGAS (cyclic GMP-AMP synthase, cGAMP synthase, =mb21d1) nav root preserves the Word navigation pane’s parenthetical aliasing verbatim.

Across the 2 sources, source-note frontmatter records 12 uncertain_span_count entries and 1 body-embedded figure asset. The single embed is the cGAS-STING Pathway figure on _181843 (data/processed/assets/by-photo/20240722_181843/figure_cgas_sting_pathway.jpg), which is preserved per the 2026-04-29 body-purity decision (docs/decisions/2026-04-29-body-purity-and-figure-only-embeds.md) because it is a non-textual pathway diagram. The 12 uncertain spans are retained as review targets.

cGAS — Senescence and the cGAS-STING Pathway

20240722_181843 anchors the chapter. The page opens with the cGAS Evidence Table Continuation (Paraquat / iPSC Correction rows covering an in-house paraquat-mouse readout, a right-side {Sliter, 2018 #699} PINK1 / PARK2 / sPD serum-cytokine note with a Korean (IFNβ1는 비인급?) caveat, and a Parkin KO iPSC-DAn row recording STING not detected and cGASi (tool) non-effects), then the Sliter 2018 Mouse / STING Deletion Table that sets the EE-induced mitochondrial- stress framing across PARKIN-/- / Pink1-/- and matched Prkn-/-; STING… / Pink1-/-; STING… deletion genotypes for pS65-ub, Mt-keima, serum cytokines, serum mito-DNA, and cGAMP (Heart, LCMS) rows. Three callout blocks below the table record the STING deletion → ↓ Inflammation arrow, the Parkin-deficient mutator mice rescue paragraph, and the 2015 Gao Trex1-/- cross-reference. Specific cell symbols (= STING / = TBK1 / = IRF3 / ↑ cleaved caspase-3; PARKIN-/- pS65-ub and Mt-keima marks; cytokine and mtDNA arrow cells) stay on the canonical page rather than being re-quoted here.

The Biomarker / Readout Notes record open questions on dsDNA segmentation in PD patients, a 20200930 Masato cGAS-protein LCMS- feasibility note, the ISG는 너무 다양하니 부적합하겠군 caveat, a diurnal / HV-non-activation caveat for cGAS PET, and Type I IFN / TNF-a / IL-12 cytokine-candidate selection. The cGAS-STING Pathway figure is the page’s single body-embedded asset and is preserved on the canonical page only (not re-embedded here per the 2026-04-29 body-purity decision); the accompanying transcribed legend lists the cytosolic-DNA inputs, the Damaged Mitochondria → mtDNA → cGAS and ATP / GTP → cGAMP arrows, the STING / Golgi / TBK1 / IKK / IRF3 / NF-kB / Type I IFN nodes, and a Diabetes 2019; 68(6) source citation — readers should open the canonical page rather than rely on a re-quote here.

The mito damage + senescence table pairs a Parkin loss (PARK2 KO iPSC-DAn) row and a Stress (eg paraquat) (paraquat-injected mouse brain) row across the mitochondrial damage / mitochondrial DNA release / cGAS-STING / senescence / type I IFN / inflammation / neuronal loss columns; the Stress row preserves a (Fukushima, 2002 #1018) aside (with a line-wrap- inferred bee[n] token) and distinguishes Nuclear dsDNA release from mtDNA. The Executive Summary cGAS block carries the SharePoint pointer, a selectivity note on the in-house compound’s binding to activated vs non-activated cGAS, and a Niigata-univ- collaboration-20210129 expression-distribution note.

The Senescence narrative provides the SASP basic hypothesis, Chinta 2018 #936 postmortem-sPD evidence in SNpc and astrocytes, a hypothesis arrow chain (Stress → injured/dying cells release dsDNA → … → ↑ neurodegeneration) with the js: I can't find this in Chinta 2018 annotation preserved verbatim, an In-Vitro paraquat → human-iPSC-astrocyte block, a Conditioned-Medium PQ-senescent- astrocyte → DAergic-neuronal-viability follow-up, and a Mouse-Model selective-senescent-cell-deletion paragraph. The MOA Integrated block at the bottom is recorded with only the first rows visible per the source’s format_notes (rest cut at the bottom edge). 11 Uncertain Spans. Sliter-2018 PARK2 / PINK1 / mtDNA biology, the mito damage + senescence Parkin-loss row, and the senescence / Type I IFN / SASP cytokine biology are delegated per the boundary table.

cGAMP — Assay Development & Monthly Update

20240722_181847 opens with a Partial Preceding cGAS Row (bottom edge of the prior-page table) and short cGAS / cGAMP primers (cytosolic DNA sensor; 2’3’-cGAMP as the major isoform). The Assay Development And Monthly Update wide table is the chapter’s centrepiece and tracks two parallel modality streams from 202002 through 202103: a Biology column, a DMPK Iwasaki Shinji LC/MS column, and an NSTM MSD (Meso Scale Discovery) column with a goal row pinning targets (0.25 pmol/mL from TREX-KO heart; LLoQ < 10 pg/mL = 10 nM). The table preserves the MSD LLoQ trajectory across early months, a Nishi-Toshiya 20200729 caveat about signal-identification status, the 202008 isoform-comparison plan, the 202009 2’3’-cGAMP specificity confirmation, the 202009 Biology cell on Park2-KO iPSC- DAn / paraquat-mouse-midbrain cGAS protein, the 20201007 NSTM HV CSF-cGAMP block (with the headline mean ± SD value and a Kamiguchi: this is BFA. annotation), the 20210217 m-meeting plan for a 20-CSF feasibility study and a nano-LC peak-separation plan, and a 202102 NSTM cell with a strikethrough revision flagged as the page’s only Uncertain Span. Specific monthly cell values, dose / concentration tokens, and patient-stratification candidates (sPD / Parkin-PD / PINK1-PD) stay on the canonical page rather than being re-quoted here.

The LOD And LLOQ Notes block records the LoD and LLOQ definitions, a Js: LLOQ seems more important than LOD annotation, and a LOD can be lower than LLOQ ordering. The STING primer follows (ER protein, central regulator of type I IFN response to cytosolic DNA). The cGAS Inhibitor / Pathway Notes row pair lists baricitinib (Olumiant, JAK1/JAK2 → STAT pathway) and RU.521 ({Chin, 2019 #765} active-site cGAS inhibitor; ↓ type I IFNs; flagged as having no effect on human cGAS), with a trailing RIG-I: cytosolic RNA sensing reference. The page closes on the AGS Transition stub heading, whose body is delegated to the parkin-side _181851 chapter per the boundary table. 1 Uncertain Span. Bioanalytical LC/MS / MSD methodology, the HV CSF-cGAMP value as a biomarker benchmark, patient-stratification options, and the cGAS-inhibitor program rows are delegated per the boundary table.

Source Table

All 2 sources, in capture-time order, with the per-page uncertain- span and embedded-image counts copied verbatim from source-note quality_metrics. nav path is the full nav_path recorded in the source note (joined by >).

stem	nav path / heading	source note	canonical	uncertain spans	embedded images
20240722_181843	cGAS (cyclic GMP-AMP synthase, cGAMP synthase, =mb21d1) > Senescence	note	md	11	1
20240722_181847	cGAMP (cyclic GMP-AMP) > Assay development and monthly update	note	md	1	0

Totals across the 2 sources: uncertain_span_count = 12, embedded_image_count = 1. These are review surface area; the single embed (figure_cgas_sting_pathway.jpg on _181843) is preserved per the 2026-04-29 body-purity decision because it is a non-textual pathway diagram.

Uncertainties Carried Forward

Specific uncertainty hot spots worth checking on the canonical pages before any downstream extraction (each axis section above counts the per-page totals; this list captures the cross-page issues):

• _181843 Paraquat row equality / arrow relations (= STING, = TBK1, = IRF3, ↑ cleaved caspase-3) flagged as high-risk due to narrow table cells and line wrapping; the right-side {Sliter, 2018 #699} Korean note (IFNβ1는 비인급?) is partly blurred; the STING-deletion genotype labels Prkn-/-; STING… / Pink1-/-; STING… use superscript / subscript notation too small to fully resolve; the Sliter-table cells for pS65-ub and Mt-keima under PARKIN-/- carry small symbols that cannot be confidently transcribed as +, -, or another mark.
• _181843 dsDNA Biomarker / Readout question — high dsDNA segmentation in PD patients? flagged because segmentation splits across lines; the cGAS-protein note low normal brain is left as visibly typed (could mean low in normal brain).
• _181843 mito damage + senescence table: Fukushima, 2002 #1018 citation is cramped and bee[n] marks an inferred missing character from line wrap; the senescence paragraph flags Beausé jour / Beauséjour citation spelling and the Greek-letter tokens SA-β-gal and 53BP1 as high-risk OCR items; the MOA Integrated block’s bottom table is visible only at the first rows per the source’s format_notes (Bottom of body opens the MOA Integrated block; only the first rows are visible and the section continues into 20240722_181847).
• _181843 nav-vs-status drift — the navigation pane visibly highlights Senescence while the status bar still shows generic Supplement / Positive vs Negative entries; nav / body evidence is treated as stronger. The page label Page 44 of 50 is triangulated by Apple Vision / PaddleOCR / status bar but flagged because nearby synthesized pages have shown document / page-count inconsistencies.
• _181847 202102 NSTM cell strikethrough boundaries (The TSHO MBM team ~~also successfully … They are~~ is planning to measure cGAMP in PD patient's CSF …) — Markdown uses ~~…~~ for the visible deleted phrase, but the exact revision boundaries should be checked on the canonical page.
• _181847 AGS Transition heading is a stub on this page; the body bullets continue onto _181851 (filed under sections/parkin by its AGS … / cGAS transition > Parkin > PARK2 Gene (=PRKN) nav root). This is a section break across photos rather than a value uncertainty, but readers extracting AGS-specific claims should walk the boundary into parkin.

Related Pages

• cgas-cgamp — section index for all 2 sources
• parkin / parkin — own the AGS / cGAS-transition _181851 page (AGS/ALS/cGAS to Parkin/PRKN Transition, ALS with cGAS, Rationale, Mechanism) that the AGS Transition stub on _181847 opens; also own Sliter 2018 #699 PARK2 / PINK1 / mtDNA-release biology and the Parkin-loss row of the mito damage + senescence table on _181843
• parkn-gt — owns the PARKN GT (PFR-4249-100) program-side narrative that consumes Parkin-KO iPSC-DAn Correction rows and pS65-Ub / Mt-keima readouts
• mitochondria — owns mtDNA / mitophagy / oxidative-stress / 31P MRS biology that the Damaged Mitochondria → mtDNA → cGAS arrow and mito damage + senescence Stress row consume
• inflammation / nlrp3-inhibitor — own type-I-IFN / SASP / IL-6 / IL-1α / MMP-3 / p16INK4a / lamin B1 senescence biology, microglia / TNFα / NLRP3 / Complement / pyroptosis disease-side narrative, and the cytokine-candidate selection that Type I interferon? / TNF-a and IL-12 imply
• lysosome-autophagy — sibling topic; owns LysoTracker / DQ-Red BSA / autophagy-marker assay vocabulary and BMP / LIMP2 / Cathepsin biomarker landscape that the cGAMP MSD-vs-LC/MS assay strategy parallels
• biomarkers-outcomes — sibling topic; [BIOMARKER] validation / qualification framework, plasma-vs-blood / serum / CSF analyte-selection criteria, MJFF Phases of Assay Development; HV CSF-cGAMP 4871.3 ± 790 pg/mL (N=5) ≈ 7.22 nM benchmark and patient-stratification options (sPD / Parkin-PD / PINK1-PD) feed there
• molecular-biology — sibling topic; LC/MS bioanalytical methodology, MSD immunoassay specificity, 2’2’- vs 2’3’- vs 3’3’-cGAMP isoform discrimination, cGAS protein expression LCMS-feasibility (Niigata univ collaboration 20210129)
• clinical-pd — sibling topic; Pipeline-of-PD comparator inventory and the sPD / Parkin-PD / PINK1-PD stratification candidates that the 20201007 NSTM block flags
• therapeutic-programs — program-routing map; the cGAS-inhibitor program rows (Takeda compound; baricitinib reference; RU.521 reference) and the Our compound binds activated Cgas selectivity note remain Entity Backlog Candidates and are not promoted to entity pages here
• alpha-synuclein — sibling topic (Tier 1); aSyn / Lewy-pathology coverage that downstream cGAS-PD MOA hypotheses (paraquat-induced senescence → ↑ pro-inflammatory factors → neurodegeneration) connect to
• inflammation / mitochondria / biomarkers-outcomes — sibling sections with adjacent disease-side and biomarker material
• cgas-cyclic-gmp-amp-synthase-cgamp-synthase-mb21d1 — cGAS (cyclic GMP-AMP synthase, cGAMP synthase, =mb21d1) first-nav_path index
• cgamp-cyclic-gmp-amp — cGAMP (cyclic GMP-AMP) first-nav_path index
• ags-aicardi-goutieres-syndrome-cgas-transition — AGS (Aicardi-Goutieres Syndrome) / cGAS transition first-nav_path index (owned by sections/parkin via _181851)
• source-catalog — all 447 sources in capture order
• nav-path-index — 376 distinct nav_paths