Parkin

This topic page reorganises the 46 source notes filed under parkin 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 treats Parkin as four overlapping problems. (1) The protein and gene itself: chromosome 6, ubiquitously expressed, an ubiquitin E3 ligase with a defined activation cycle and a long substrate list (20240722_181851, 20240722_181859, 20240722_181903). (2) Parkin PD as a clinical and population genetics question: variant catalogues, penetrance, prevalence, autopsy/imaging phenotype, and patient cohorts (20240722_181907 through 20240722_181950). (3) The mitophagy / pS65-Ub axis as the proximal disease biology and as a candidate biomarker (20240722_181954, 20240722_181958, 20240722_182001 through 20240722_182007). (4) PARKN GT (PFR-4249-100), the AAV9-Parkin gene-therapy program: in-vivo delivery evidence, executive summary, decision tree, biomarker matrices, NHP studies, sample-size logic, and a bioanalytical assay package (20240722_182011 onward). PINK-1 (20240722_182116) and the GAPFREE3 / Preclinical-support radioligand-binding work (20240722_184103, 20240722_184130, 20240722_184138, 20240722_184142) sit alongside the Parkin axis as related, often shared, evidence.

Source Coverage

46 source notes are assigned to the parkin section. They sit across four nav_path clusters and seven additional first-level nav roots, all collapsed into this topic:

nav root (first nav_path entry)sourcescovered axis
Parkin27Parkin protein, Parkin PD, mitophagy/pS65-Ub, PARKN GT (introductory through NHP)
Parkin, (trailing comma; nav typo)4Parkin PD variant tables and PARKN GT TM/Assays/PINK-1 transition
PARKN GT (Takeshi Hioki, PFR-4249-100)8PARKN GT NHP bioanalytical / target-validation / PE / PET / Safety / TM Assays
PINK-11PINK-1 protein / animal models / YOPD gene table
AGS (Aicardi-Goutieres Syndrome) / cGAS transition1shared page that opens the Parkin / PARK2 Gene (=PRKN) section after AGS/cGAS
Preclinical support2Fibroblast PARK2 lines, MC1 PET budget, sample preparation
GAPFREE32Saturation analysis on PARK2 fibroblasts, ARG, Scatchard, Tsukada 2014 reference
GAPFREE3 (iPSC, Yuya Kunisada)1sPD / iPSC cohort note adjacent to Cambridge organoid collaboration

For exact nav_path strings and headings see parkin and parkin; the Parkin and Parkin, variants are merged in the by-nav index per the 2026-05-01 P1 fix (log).

Across the 46 sources, the source-note frontmatter records 186 uncertain_span_count entries and 32 body-embedded figure assets. They are retained as review targets, not resolved here.

Parkin Protein, Gene, And KO

20240722_181851 introduces PARK2 (PRKN) at 6q26 with 12 exons, 8 mRNA transcript variants, and 26 splice variants; variant 1 (1398 bp CDS) is the program’s construct. Homology with rhesus is 99%, mouse 94% (per the embedded PRKN gene/expression figure). Parkin protein concentration in human brain is reported by ELISA as 771 (500-1500) pg/mg total protein, by SMCxPro as mean 6.92 pg/mg total protein (n=5, SD 8.894, 80% CI 1.82-12), and by LC/MS as 3590 - 9052 pg/mg protein; CSF SMCxPro values run 0.7-2.5 pg/mL (n=7); NHP CSF gives No signal and the source note flags assay method text (antibody catalog numbers, ug/MP mg) as Uncertain Spans.

20240722_181855 catalogues commercial Parkin proteins, ADDP in-stock proteins, homology, and KO Parkin. 20240722_181859 maps location/states/structure/substrate transitions including the activation state diagram, substitutions/deletions/multiplications map, pathogenic mutation domain map, and basic protein facts. 20240722_181903 lists substrates (VDAC1, PARIS (ZNF746), Miro, AIMP2, synphilin-1, Mfn1/2, Tubulin, SYT11, p53, parkin itself, aSyn (?)) and animal models including (Noda, 2020 #701), (Palacino, 2004 #726), (Stevens, 2015 #1031), (Pinto, 2018 #934), (Lu, 2009 #930) Parkin-Q311X Tg, plus 6-OHDA rat/mouse and (Bian, 2012 #704) Parkin Tg. The source flags Noda percentages and Stevens overlap as uncertain.

Parkin PD: Prevalence, Variants, Phenotype, Imaging

Prevalence framing is most direct in 20240722_181903 and 20240722_181907: YOPD (<50) is 4-10% of total PD (Camargos 2009 #689); Kilarski, 2012 #692 gives 15.5% of familial and 4.3% of sporadic cases; the 20200924 tDIB arithmetic lands at 0.33% (familial) + 0.34% (sporadic) = 0.67% biallelic young-onset Parkin-PD of total PD, or roughly 402,000 cases worldwide. Late-onset homo/compound-heterozygous Parkin-PD is estimated at ~0.1% of total PD. The rare-disease note in 20240722_181907 records 0.65% (= 0.31 + 0.34) and is flagged as uncertain because that does not match the 0.33 + 0.34 figure on the same page.

Variant evidence lives across 20240722_181910 (GE/GMS participant mutation table; MP-PD reanalysis), 20240722_181914 (AMP-PD LoF

  • deleterious missense carriers, Page 2020 #1751 demographics), 20240722_181917 (PRKN exon/domain map, ROPAD notes), 20240722_181921 (variant annotation continuation, missense functional alterations figure, Yi ACMG-AMP criteria), 20240722_181925 (ACMG-AMP / Yi pathogenic-vs-benign criteria, Masten 2018 review, Morais 2016 Portugal), 20240722_181928 (Klein 2012 review, Akhit 2016, Darvish 2013 Iran), and the ClinVar-style rows in 20240722_181932, 20240722_181936, and 20240722_181939. These pages carry many Uncertain Spans (10, 9, 6, 11 respectively) for ClinVar / HGVS / structural-variant cells, so specific cell values should be re-checked against the source page rather than re-quoted from this topic.

Heterozygous-carrier risk and neuropathology are in 20240722_181943 (population estimates and penetrance, regional neuronal loss and gliosis figure, Schneider 2017) and 20240722_181947 (Schneider 2017 PARKIN autopsy reports and Alcalay 2014 EOPD PARKIN cognitive/demographic table). Imaging progression and treatment response are in 20240722_181950: DATSCAN / 18F-DOPA longitudinal notes, Pellecchia 2007 FP-CIT SPECT, DTI, neuromelanin MRI, MDSGene reported signs and symptoms, and a Parkin/PINK1 mitophagy diagram.

Mitophagy And pS65-Ub

20240722_181954 is the mitophagy evidence matrix (Parkin/PINK1, pS65-Ub detectability, extracellular mitochondrial expulsion figure, Parkin in sPD). 20240722_181958 is the densest pS65-Ub page and the one most directly used as biomarker rationale: it embeds Hou 2018 #819 figures (advanced PD > early PD > old normal > mid-aged normal > young normal = Parkin-PD = PINK1-PD; reduced or absent p-S65-Ub in PRKN/PINK1 SN), Shiba-Fukushima 2017 phospho-Ub IHC, and a NBB brain/CSF pS65Ub-K48 plot. The source records NBB sample values for PARK2-1 / PARK2-2 (CSF 2.3, 3.3; brain 7.3, 4.4), sPD (CSF 6.4±0.9*, brain 11.14±3.01*) and HC (CSF 6.4±3.4*, brain 16.78±8.06*); all plus/minus values, sample counts, and group labels are flagged as image- primary uncertain. The next-step plan separates Detection assay platform, Disease relevance, (Proximal) pathway relevance, and Treatment relevance (level change in response to WT exogenous parkin via AAV).

20240722_182001 frames the biomarker discovery questions (ubiquitin linkage basics, pS65-Ub / Parkin substrates / TE biomarker / patient selection, fibroblast mitochondrial-function rationale, MC1 density and activity de-risking, respiratory complex stoichiometry, Mortiboys / Zanellati / Pacelli / van der Merwe / Grunewald / Zilocchi evidence). Fibroblast and iPSC mitochondrial evidence continues in 20240722_182004 (Zilocchi 2020 PARK2 fibroblast continuation, mitochondrial proteomics, PhRET proposal, Koentjoro mitophagy and rescue, mtDNA / ER-mitochondria, iPSC evidence summary). 20240722_182007 is the fibroblast translation plan and the table of Parkin gene/protein delivery evidence in animal models.

PARKN GT (PFR-4249-100): Program Synthesis

PARKN GT is the AAV9-Parkin gene-therapy program led by Takeshi Hioki, with program code PFR-4249-100. The program-level entity page is parkn-gt; this section only summarises how PARKN GT material is distributed across the topic sources.

The introductory pages cross the Parkin-PD → PARKN GT boundary. 20240722_182011 carries the Parkin gene/protein delivery in-vivo continuation, iCP-Parkin (Chung 2020, Cellivery), Bian 2012 MPTP TG, and the PARKIN GT executive-summary expression timeline (LGE 2020 Oct, PE 2021/12, CN 2023 10, CS 2024/06, IND 2025/86; the last token is uncertain). It records 9 expression-cassette candidates (rAAV9-PK031, PK022, PK030, PK012, PK013, PK023-026) and the in-vivo Parkin-KO mouse expression test (4 m old, 6 cassettes with AAV9, ICM, single injection, n=7 per cassette, 1.5 m post-injection analysis; vector dose (1x10**) vg/10 uL is uncertain).

20240722_182014 is the PARKN GT executive summary / clinical strategy / GBA PET rationale page, including the AAV9-Parkin expression-comparison figure (PK012, PK044, PK045, PK046 as % of PK012; dose annotation 1.6x 10^? VG/injection flagged uncertain), the iPSC-DA infection plot, the AQB1 (Parkin GT AQB1 for PRC PE 20211111.pptx) and budget/FTE artifact links, and the preclinical/prodromal/symptomatic decision matrix (decision notes: Onset variable. Accepted only to pathogenic variants; Large trial needed, hetero not plausible).

20240722_182018 holds the GBA-PET-rationale carry-over (CSF GBA-protein and CSF GBA-activity caveats: No healthy data, No consensus on CSF GBA BL level in PD (only Mullin 2020 Ambroxol P2), LLOQ; 0.56 umol/L/d), the GBA expression evaluation imaging figure, and the Cellivery iCP-Parkin / Mission USP30 (MTX115325) / MitoCoP / DBS+PRkn competitor / strategy table. It includes Yi 2019 protein-level note that point mutation carriers may have unchanged or even increased Parkin protein, with exonal rearrange at 0% and point mutation at 50% giving roughly 25% mean.

20240722_182021 embeds the PARKIN GT decision tree and draft timeline (Mar 9, 2022) — gates PE Feb 2022 / CN Mar 2023 / CS Mar 2024 / IND Aug 2025, decision criteria >=20% recovery of mitochondria function and >=20% DA neurons expressing Parkin in NHP SN, and the biomarker expected-change matrices for MPTP and Parkin KO mice across CSF Parkin protein, CSF Parkin mRNA, CSF pS65-Ub, and Brain MC1 proteins.

The PRC1 dataset, FXN GT benchmark, and the in-vivo MPTP / 6-OHDA / α-Syn PFF / R275W tables are in 20240722_182025, including the rAAV9-hSYN1-coPRKN (PK041) and hPGK1-coPRKN (PK044) constructs at 1x10^8-1x10^10 vg/brain, the early reads (~20% DA neuron recovery in SN and STR (IHC), ~30% DA neuron recovery in STR (WES), α-Syn PFF 1M ~23% DA neuron recovery), the IP-filing note, and the KOL-Hattori notes about astrocyte immaturity / lactate consumption / dancing-feet dyskinesia.

20240722_182029 extends the KOL block (Hattori → Schlossmacher redox / GSH:GSSG → Christine Klein 31P MRS, aSyn seeding, neuromelanin imaging) and lays out the high-level biomarker plan (Target Engagement: CSF Parkin protein, Parkin PET; Pharmacodynamic: pS65-Ub; Imaging: MC1 PET; Disease Related: DaTScan; explicit note that aSyn-related biomarkers are not planned for this project because aSyn pathology is rarely observed in the target population).

Natural-history strategy and sample-size are in 20240722_182033: MJFF / PPMI / Leuven MC1 PET proposal, dated KOL notes (Cristian/Jamie Eberling, Koen Van Laere), the PRKN longitudinal observational study design (Part 1 cross-section HC vs PRKN-PD, Part 2 longitudinal; N ~ 25 with 10 healthy control and 15 symptomatic PD; 3-5 years), and partial sample-size figures (e.g. 20% reduction and 50% CV results in a sample size of 21 at 80% power, one-sided alpha = 0.10). Cohort feasibility: PDGene (PRKN homozygotes/compound heterozygotes: n=45; PRKN heterozygous: n=79), GP2, ROPAD/Centogene (>200), Leuven (5 subjects), PPMI (6 (?)). 20240722_182036 continues sample-size and starts NHP studies current plan with promoter / cassette notes, ROA / dose / criteria, pilot / device, NHP route / dose table, and cost / schedule.

20240722_182040 is the detailed NHP plan (ROA neurosurgery pilot, 1M NHP biodistribution slot at NBR 047-052, Injection Feb/Mar 2023, Necropsy Mar/Apr 2023, Report (IHC/ISH) Jun 2023; AAV9 PK044 with PGK1; pilot device choice between Neurochase and Clear Point; full route/dose table; CSF sampling protocol, aliquoting, shipment to TSHO; the NBB / PrecisionMed correlation plan with target 1 pg/mL normal CSF Parkin).

PARKN-GT-only pages whose first nav root is the long PARKN GT (Takeshi Hioki, PFR-4249-100) cover the bioanalytical method to differentiate human and monkey Parkin (20240722_182043, 20240722_182046), quantitative BM criteria and target validation (20240722_182050), the PE I Parkin-binding assay HTS history and 11-candidate list (20240722_182053), the multi-year 20210615 → 20220715 binding-assay development log (20240722_182057), the binding-assay termination memo and PE I Imaging GBA plan (20240722_182100), the Safety / Sharefolder / PGRN / Assays page (20240722_182106), and the TM Assays / pS65-Ub assays / IVC / Parkin activity assay page (20240722_182110). 20240722_182113 collects the trailing-comma Parkin, axis from TM > Assays > IVC > Parkin activity assay? > TMQB > TPP/TCP > Unmet Needs > Vector production > PINK-1 and acts as the PARKN GT → PINK-1 transition.

PINK-1

20240722_182116 is the single PINK-1 page in this section. Pathogenicity is partly carried over from the previous photo (nonsense mutations in 14%, Only one-fifth of mutations are classified as definitely pathogenic; prevalence per Kilarski 2012 #692 weighted-pooled 3.7% of EOPD, homozygous 81.8%, with much higher rates in Asian than white patients). The page covers PINK-1 protein (mitochondrial intermembrane space and membrane), phenotype (Early onset 32.4 y, slower disease progression, good response to levodopa, less spasticity / pyramidal signs / hyper- reflexia than Parkin PD), pathology (nigral neuronal loss and gliosis with rare LBs), animal models (Gispert 2009 #942, Kitada 2007 #943, Alzforum), the YOPD-PD genes table (16 genes; 4 mt, 3 lysosome, 2 ubiquitination), the late-onset PD genes table (GBA 2.3-9.4%, LRRK2 ~1%, TMEM175, SNCA, PINK1), and the Kalia and Kalia α-synuclein / Lewy pathology Table 1 (Parkin: protein-in-LB +, LB-associated +/-). The page records 7 Uncertain Spans (top continuation, Kilarski cohort line, Kasten line, animal-model row endings, Kalia table cut at edge).

Clinical Cohorts And Sample-Size

The clinical / cohort / sample-size strand spans Parkin PD pages 20240722_181907 (GE/GMS biomarker cohort proposal: 11 GE participants, 20 sPD, 20 HC, mitochondrial biomarkers pS65-ub, Parkin, TOM40/20, mt DNA damage, mtDNA copy number, ATP) and the PARKN GT pages 20240722_182025, 20240722_182029, 20240722_182033, and 20240722_182036 for the PRKN longitudinal observational study, sample-size estimation, MC1 PET sub-study options, and KOL/cohort feasibility.

For Parkin-PD genetics-trial design, 20240722_181910 holds the Genomics England participant mutation table and sample matrix that feeds into the GE biobank discussion. The DBS+PRkn-only-with-placebo N=12 to 14, DBS-only N=6, and combined N=12 trial-design notes are at 20240722_182018 / 20240722_182021. All of these are records of considered trial designs, not committed designs.

Preclinical Support And MC1 PET Radioligand Work

The Preclinical support and GAPFREE3 photos in this section are MC1 PET / [3H]BCPP-EF radioligand-binding work performed on the Parkin-PD fibroblast lines (ND31618 R42P, ND30171 R42P / EX3DEL, ND40078 R275W/R275Q, ND29369 R275W, plus healthy controls GM01650, GM03652, 106-05n, CC-2511):

  • 20240722_184103: saturation- binding analysis Q&A (Bmax/Kd assumptions); fibroblast inventory including the four NINDS Parkin-PD lines, sPD lines (ND37609, ND35302, ND37132, ND30159), and the red-banded summary inventory at the bottom.
  • 20240722_184130: Preclinical support budget, sample-preparation plan (8 control / 8 Parkin-PD; N=3; Glucose & Galactose; whole cell vs mito-enriched), shipping table (Takeda Fujisawa / San Diego / Cambridge MA), and the Update 20210423 (Taka) / Update 20210806 (Yoshirou) blocks with the 3H-BCPP-EF homogenate protocol for GM01650 / GM03652.
  • 20240722_184138: saturation analysis only HC GM01650, concentration response curve (Two-Site Fit, Hi IC50 = 9 nM (Ki ~5 nM), Lo IC50 = ~400 nM), and the start of Saturation analysis (Main).
  • 20240722_184142: the ARG (autoradiography) sub-section, Scatchard plot derivation, and the Tsukada 2014 #883 BMS / BCPP-EF / BCPP-BF reference IC50/Ki table (BCPP-EF Ki = 2.31 nM).

These four pages tie the Parkin-PD fibroblast collection to the MC1 PET biomarker rationale that PARKN GT carries forward. The shared 20240722_182004 / 20240722_182007 Zilocchi / Pacelli / Koentjoro fibroblast literature is the upstream rationale for the choice of these particular cell lines.

20240722_183345 is a GAPFREE3-iPSC page (300 sPD patients, iPSC; 150 cases, Yuya Kunisada) inside the iron / Cambridge organoid arc; it appears in the parkin section because its first nav root is GAPFREE3 (iPSC, Yuya Kunisada) and the page itself names PARK2 as a cohort axis, even though its dominant body content is iron physiology.

Source Table

All 46 sources, in capture-time order, with the per-page uncertain-span and embedded-image counts copied from front matter. nav path is the full nav_path recorded in the source note.

stemnav path / headingsource notecanonicaluncertain spansembedded images
20240722_181851AGS (Aicardi-Goutieres Syndrome) / cGAS transition > Parkin > PARK2 Gene (=PRKN)notemd31
20240722_181855Parkin > Parkin protein > KO Parkinnotemd40
20240722_181859Parkin > Parkin protein > Location / States / Structure / Substrates transitionnotemd53
20240722_181903Parkin > Parkin protein > Substrates (& function) of Parkin > Parkin PDnotemd41
20240722_181907Parkin > Parkin PD > Clinical strategy > Natural Hx studynotemd10
20240722_181910Parkin > Parkin PDnotemd20
20240722_181914Parkin, > Parkin PDnotemd40
20240722_181917Parkin, > Parkin PDnotemd41
20240722_181921Parkin > Parkin PDnotemd21
20240722_181925Parkin > Parkin PDnotemd101
20240722_181928Parkin, > Parkin PDnotemd50
20240722_181932Parkin > Parkin PDnotemd90
20240722_181936Parkin > Parkin PDnotemd60
20240722_181939Parkin > Parkin PDnotemd110
20240722_181943Parkin > Parkin PDnotemd81
20240722_181947Parkin > Parkin PDnotemd91
20240722_181950Parkin > Parkin PDnotemd45
20240722_181954Parkin > Parkin PDnotemd81
20240722_181958Parkin > Parkin PD > pS65-Ubnotemd44
20240722_182001Parkin > Parkin PDnotemd101
20240722_182004Parkin > Parkin PDnotemd13
20240722_182007Parkin > Parkin PDnotemd100
20240722_182011Parkin > PARKN GT (Takeshi Hioki, PFR-4249-100)notemd40
20240722_182014Parkin > PARKN GT (Takeshi Hioki, PFR-…) > Executive summarynotemd31
20240722_182018Parkin > PARKN GT (Takeshi Hioki, PFR-4249-100) > Clinical strategynotemd21
20240722_182021Parkin > PARKN GT (Takeshi Hioki, PFR-4249-100)notemd22
20240722_182025Parkin > PARKN GT (Takeshi Hioki, PFR-4249-100)notemd10
20240722_182029Parkin > PARKN GT (Takeshi Hioki, PFR-4249-100)notemd20
20240722_182033Parkin > PARKN GT (Takeshi Hioki, PFR-4249-100) > Natural Hx study > Sample size estimationnotemd22
20240722_182036Parkin > PARKN GT (Takeshi Hioki, PFR-4249-100) > Natural Hx study > Sample size estimation > NHP Studies > Current plannotemd22
20240722_182040Parkin > PARKN GT (Takeshi Hioki, PFR-4249-100) > NHP Studies > Current plannotemd00
20240722_182043PARKN GT (Takeshi Hioki, PFR-4249-100) > NHP Studies > Bioanalytical method to differentiate human and monkey Parkinnotemd10
20240722_182046PARKN GT (Takeshi Hioki, PFR-4249-100) > NHP Studies > Bioanalytical method to differentiate human and monkey Parkinnotemd20
20240722_182050PARKN GT (Takeshi Hioki, PFR-4249-100) > Natural Hx study > Quantitative BM criteria / Target validationnotemd00
20240722_182053PARKN GT (Takeshi Hioki, PFR-4249-100) > PE > PETnotemd00
20240722_182057PARKN GT (Takeshi Hioki, PFR-4249-100) > PE > PETnotemd20
20240722_182100PARKN GT (Takeshi Hioki, PFR-4249-100) > PE > PETnotemd30
20240722_182106PARKN GT (Takeshi Hioki, PFR-4249-100) > Safety > Sharefoldernotemd20
20240722_182110PARKN GT (Takeshi Hioki, PFR-4249-100) > TM > Assaysnotemd10
20240722_182113Parkin, > TM > Assays > IVC > Parkin activity assay? > TMQB > TPP/TCP > Unmet Needs > Vector production > PINK-1notemd40
20240722_182116PINK-1notemd70
20240722_183345GAPFREE3 (iPSC, Yuya Kunisada) > Mid-brain organoids with FTD-tau (University of Cambridge) > Iron > Normal roles of iron > Normal distribution of iron > Normal physiology > Ferritinnotemd40
20240722_184103Preclinical support > Fibroblasts > PARK2 cellsnotemd50
20240722_184130Preclinical supportnotemd60
20240722_184138GAPFREE3 > Preclinical supportnotemd30
20240722_184142GAPFREE3 > Preclinical support > ARGnotemd40

Totals across the 46 sources: uncertain_span_count = 186, embedded_image_count = 32. These are review surface area, not corrections that have been applied here.

Uncertainties Carried Forward

This page deliberately does not paraphrase variant tables, ClinVar rows, NBB plus/minus values, decision-tree gate logic, draft-timeline schedule fields, or the bioanalytical method comparison. Those are image- or table-primary on the source pages and the source-note frontmatter records non-zero uncertain_span_count for them. Specific uncertainty hot spots worth checking before any downstream extraction:

The 0.65% vs 0.33+0.34=0.67% Parkin-PD prevalence arithmetic difference on 20240722_181907 is preserved verbatim and not reconciled.