Parkin Substrates, Animal Models, And Parkin-PD Prevalence

Substrates And Functions Of Parkin

substrate / label	function / notes	pathway / category
VDAC1 / preceding row fragment	VDAC1 is one of the most strongly ubiquitylated PARKIN substrates (Ordureau, 2018 #698); Quantification of VDAC1 ubiquitination 가능하다는 것 같은데 ? (is this Fig 4G ?) (Ordureau, 2018 #698); caveat notes conflicting reports, with evidence both for (Geisler et al., 2010) and against (Narendra et al., 2010a) VDAC involvement in PARKIN-dependent mitophagy.
PARIS (ZNF746)	75, 76, 181, 182, 190, 191]; mitochondrial biogenesis by ubiquitination of PARIS (PGC-1_[Peroxisome proliferator-activated receptor gamma coactivator-1-alpha] transcriptional repressor, Lee et al., 2017)
Miro	mitochondrial movement by regulating Miro (Wang et al., 2011; Gaweda-Walerych and Zekanowski, 2013)
aminoacyl tRNA synthetase complex interacting multifunctional protein 2 (AIMP2),
synphilin-1 (	an alpha-syn interacting protein that is enriched in the core of Lewy bodies and ubiquitinated by parkin in a manner abolished by familial PD-associated mutations.
CDC-rel1, cyclin E, , Pael-R, XI, sp22
Mitofusins Mfn1 and Mfn2,	which are large GTPases that promote mitochondria fusion into dynamic, tubular complexes that maximise efficiency of oxidative phosphorylation
Additionally, Parkin contains a C terminal motif that binds PDZ domains. the p38 subunit of aminoacyl-tRNA synthetase complex[36] and far upstream element-binding protein 1[37] through addition of Lys48-linked poly-Ub chains	Parkin has been shown to associate in a PDZ dependent manner with the PDZ domain containing proteins CASK and PICK1	UPS
Tubulin	Axonal transport
synaptotagmin XI (SYT11)	Synaptic Vesicle fusion
P53	parkin protects dopaminergic neurons from cytotoxicity induced by PD-mimetic 6-OHDA, mediated by suppression of neuronal p53 expression and its downstream activation of the apoptotic cascade. Several PD-associated parkin mutations are localised to RING1 and might impair the ability to bind and downregulate the p53 promoter, leading to enhanced p53 expression. Parkin-mutant PD patients also exhibit a four-fold elevation in p53 immunoreactivity.
parkin itself
aSyn (?)	Parkin, has been previously demonstrated to protect against the toxic effects of alpha-syn, https://www.michaeljfox.org/grant/investigating-effect-parkin-alpha-syn-propagation

UPS
Parkin also enhances cell survival by suppressing both mitochondria dependent and -independent apoptosis.

Parkin PD - Prevalence Opening Note

Parkin PD
Prevalence

(Poorkaj, 2004 #572) 18% of familial PD (js 전체 PD의 1.8%네), However, if parkin is recessive, only 5% of early-onset cases who had compound mutations could be attributed to this locus. Mutation frequency was 0.12 (95% CI 0.04-0.19). 70% of parkin cases were heterozygous. It is unclear whether heterozygous mutations are pathogenic

Animal Models Of Parkin PD

Animal models of Parkin PD
overexpression of T240R-parkin and Human WT parkin
progressive and dose-dependent DA cell death [146].
Parkin-Q311X-DAT-BAC mice exhibit multiple late onsets and progressive

model / citation	background or model detail	mitochondrial abnormality	neurodegeneration / phenotype	Lewy body / note
PARKIN KO mice (Noda, 2020 #701)	B6;129 genetic background; Only At the age of 110 weeks, locomotor impairments, including hindlimb defects, began to show motor behavioral deficits at 110 weeks	[SN 만 봄]; Only At the age of 110 weeks mitochondrial fragmentation in DA neuron in SN, small (↓ (fig2b, by 60%) mt area) fragmented mt accumulate (↑ the number of mt per unit of cytosolic area) in both cytosol & outside cells, ↓ mt area; EM: fragmented mitochondria had normal outer membrane structure (Fig. 3A c inset), but displayed irregular inner structure, i.e., the structures of matrix and cristae were broken.	Only at 120 w old; TH+ neurons: ↓ (30%?) in SNcc, = in VTA; DA, DOPAC, HVA: ↓ (20%?) in dorsal striatum; young mice had very little phenotypes other than downregulation of DA release and upregulation of D1 and D2 dopamine receptors in the striatum; TH neurons not decreased in 48-week-old mice (원문에는 3 month 인데?) (Sato et al., 2006); 12 m: DA, DOPAC, HVA 도 Striatum 에서 안 줌 (Sato 2006); Js: 1 년째에서 별 변화 없어서 (Sato 2006) 2 년째 봤구나 (Noda 2020)	No LBs
(Palacino, 2004 #726)		[ventral midbrain including SN]; [8 m old]: ↓ MC1 proteins (24kDa subunit, -28% 아마 NDUFV2) & (30 kDa subunit, -9%, 아마 NDUFS3), ↓ (반) Cytochrome c oxidase protein (subunit Vb); continued fragment: ↓ MC1 (by 17%), 2 (by 25%), 3&4 (by 23%)-linked ATP generation; But, normal morphology	decreased abundance of a number of proteins involved in mitochondrial function or oxidative stress. Consistent with reductions in several subunits of complexes I and IV, functional assays showed reductions in respiratory capacity of striatal mitochondria isolated from parkin/ mice. Electron microscopic analysis revealed no gross morphological abnormalities in striatal mitochondria of parkin/ mice.
(Stevens, 2015 #1031)	conditional KO of Parkin in the adult mice ventral midbrain (lentivirus expressing GFPCre)	↓ (32% but overlap) mitochondria number and ↓ (40% but overlap) size, ↓ mtDNA COPy number (fig 2, ~half?)	dopaminergic neuronal loss
(Pinto, 2018 #934) PD-mito-PstI mouse		원래 In this model: mitochondrial DNA undergoes double-strand breaks in the dopaminergic neurons only, (ie acquired insult (mtDNA damage) that has been observed in normal aging.); increase in mtDNA levels (mutant and wild type).; exhibit a small but significant decrease in the number of mitochondria in the dopaminergic axons only; it did not cause a parallel increase in mitochondrial mass or mitophagy.; Our results suggest that Parkin affects mtDNA levels in a mitophagy-independent manner.; we observed a small but significant decrease in mitochondrial number only in the dopaminergic axons of ParkinKO-PD-mito-PstI mito-eYFP mice (Fig. 6C). When we analyzed mitochondrial size, we observed that the lack of Parkin led to the accumulation of larger mitochondria (Fig. 6D,E). We also examined the steady-state levels of the following two proteins associated with mitochondrial dynamics: Mfn2 and OPA1, which is involved in the fusion of the outer and the inner mitochondrial membrane, respectively. Although we did not detect changes in Mfn2 levels, there was a slight decrease in OPA1 (longform) levels in striatal homogenates from 4- and 12-month-old animals (Fig. 6B and Fig. 4-1J available at https://doi.org/10.1523/JNEUROSCI.1384-17.2017.f4-1).
(Perez and Palmiter, 2005).	B6;129 genetic background,		Perez and Palmiter claimed no loss of neurons at ages up to 22 months (88 weeks)
(Itier et al., 2003).
(Goldberg et al., 2003),
(Von Coelln et al., 2004),
Parkin KO rat / Horizon, TGRL4760	Neurobiol Dis. 2014;70:190-203
Parkin KO crossed with mutator KI mice (Dr. Youle at NIH)	(Pickrell, 2015 #702) Neuron. 2015;87(2):371-381
Parkin-Q311X Tg mice (Jax, 009090)	(Lu, 2009 #930) J Neurosci. 2009;29(7):1962-1976		Dopaminergic Neuron Degeneration, late-onset and progressive hypokinetic motor deficits	Expressing a Truncated Mutant Parkin, Accumulation of Proteinase K-Resistant aSyn
6-OHDA Rat	(Vercammen, 2006 #703)	Correction: Lentivirus-Parkin +
6-OHDA mice	Sci Adv. 2020;6(18):eaba1193
P mice	(Bian, 2012 #704)	Correction: Parkin Tg +
2-Parkin/rat aSyn expression	(Yamada, 2005 #705)

Prevalence Of Parkin Mutations

group	text
familial	familial
sporadic	sporadic

Juvenile Parkinson's (JP)
young onset PD (21-40)
recent consensus seems
% of total PD

Familial

20% of YOPD patients have at least one first- or second-degree relative with PD either in the same or antecedent generation. (Klepac, 2013 #690)
Parkin mutation: PARKIN pathogenic mutation has been found in 50% cases of familial PD and up to 15% of early onset sporadic cases in one cohort (Lücking, 2000 #693) although a recent meta-analysis (Kilarski, 2012 #692) concluded that the figure is around 15.5% of familial and 4.3% of sporadic cases.
아래로 정리 20200924 tDIB:
Kilarski 2012: 136 명의 EOPD cases 중 29 가 familial cases, so 21%
Kilarski 2012, 100 x 10% x 21% x 15.5% (the prevalence of PARK2 mutations in patients, p1525 에 3952 patients 중에서의 prevalence 라고 명시했고, patient 니까 homoz 혹은 compound heteroz 이겠지)
= 0.33% of total PD = in the us, 3,255 cases

Sporadic

Majority cases of YOPD (80% 잡으면), 다른 reference?
- PARK2 mutation: 15% of YOPD (<45)).
Then, 100 x 10% x 80% x 15% = 1.2% of total PD
 
But according to Kilarski 2012, 100 x 10% (early onset) x 79% x 4.3% (the prevalence of PARK2 mutations in patients, p1525 에 3952 patients 중에서의 prevalence 라고 명시함, patient 니까 homoz 혹은 compound heteroz 이겠지)
= 0.34% of total PD = in the us, 3,397 cases
 
(Chaudhary, 2006 #928) YOPD (N=173)중 2 명만이 HOMOz or compound hetero
 
아래로 정리 20200924 tDIB:
- 79% of YOPD cases are sporadic
  (Kilarski et al. 2012, doi 10.1002/mds.25132)
- 4.3% of sporadic YOPD have PARK2 mutations
  (Kilarski et al. 2012, doi 10.1002/mds.25132)
=> 0.34% of total PD (~3,000 cases in the US)

Combined Young-Onset Parkin-PD Estimate

Young onset Parkin-PD (Bi allelic) is 0.67% (0.33+0.34) in total PD. So 0.67% of total PD cases worldwide (6 million) is 402,000 cases.
 
(Alcalay, 2010 #691) 16.6% of YOPD patients (without regard to family history of PD.) have mutations (including (6.7%) PRKN, (3.6%) LRRK2, (6.7%) GBA, and (0.2%) DJ1 -> then Parkin-mutant PD is 3.6% of YOPD without regard to family history of PD. (ie 0.36% of total PD cases)

Uncertain Spans

location	text/status	reason
VDAC1 row	Fig 4G ?, Ordureau, 2018 #698, conflicting reports for/against VDAC involvement	Top of row is cut off and citations are small.
Noda model	TH+ neurons ↓ (30%?), DA/DOPAC/HVA ↓ (20%?), SNcc, 48-week-old vs Korean note 3 month 인데?	Numeric percentages and age interpretation are explicitly uncertain in the source note.
Stevens model	↓ (32% but overlap), ↓ (40% but overlap), mtDNA COPy number (fig 2, ~half?)	Values are visible but source note flags overlap/approximation.
6-OHDA mice figure	bar plot labels and values	Figure is too small; asset preserved rather than transcribed.