PINK-1
- nonsense mutations in 14%.
- Pathogenicity
- Only one-fifth of the mutations are classified as definitely pathogenic;
- the rest are classified as probably or possible pathogenic.
Prevalence
Kilarski, 2012 #692)
- the authors did two analysis at the same time
- UK Cohort: 136명의 EOPD 0.
- Systematic review, 25 studies with 2324 (EOPD일것) patients
- the weighted pooled proportion of cases carrying 2 pathogenic PINK1 mutations was 3.7% (parkin mutation이 8.6%이니까 그것의 43%정도네).
- The majority of mutations (81.8%) were homozygous (나머지는 compound heteryz라는 듯).
- The proportion of familial cases with mutations was 8.4% (95% CI, 2.2%-32.7%).
- the risk ratio of familial compared with sporadic cases was 9.3 (95% CI, 1.7-49.4; P ¼ .01).
- The proportion of consanguineous cases with mutations was 31.1% (95% CI, 12.7%-76.2%; Table S5).
- Compared without bred cases, this was a highly significant increase, with a risk ratio of 35.3 (95% CI, 9.6-129.0; P < 1 10_4).
- Pathogenic PINK1 mutations were much more common in Asian patients than in white patients: 13.5% (95% CI, 1.9%-94.9%) versus 0.6% (95% CI, 0.2%-1.6%), with a risk ratio of 20.3 (95% CI, 2.1%-197.7). The proportion of Latin American cases with PINK1 mutations was similar to the proportion of white cases, namely, 0.9% (95% CI, 0.1%-6.0%; Table S7).
Kasten, 2018 #708)
- 83% is homoz, 17% is compound heteroz (
- cf) Heteroz mutation
- (Aasly, 2020 #781) It was long debated whether heterozygous mutation carriers could be at risk for developing PD, although with a later onset.51,52 These early observations have not been reproduced, and reports from Tunisia, where PINK1 mutations are very common, indicate that being a heterozygous mutation carrier does not increase the risk for PD.53
기타: 250 monogenic PINK1-PD cases Worldwide (Vollstedt, 2019 #822)
Protein
- Location
- mitochondrial intermembrane space and membrane,^
- Expression
- PINK1 is a ubiquitous protein expressed throughout the human brain (Gandhi, 2006 #910)
- it is found in all cell types showing a punctate cytoplasmic staining pattern consistent with mitochondrial localization (Gandhi, 2006 #910)
- PINK1 is detected in a proportion of Lewy bodies in cases of sporadic Parkinson’s disease and Parkinson’s disease associated with heterozygous mutations in the PINK1 gene,
Phenotype
- Similar to Parkin PD
- Early onset (32.4 세), slower disease progression, and good response to levodopa, (2009 Ferraris)
- But less spaciticity, pyramidal signs or hyperreflexia than Parkin PD
- Rare cognitive decline
Pink1 mutation carriers
- Phenotype
- Subtle parkinsonian signs but still ‘asymptomatic’ (Weissbach, 2017 #782)
Pathology
- Neuronal loss
- Nigral neuronal loss and gliosis, with a few LBs and Lewy neurites identified in the substantia nigra (SN), nucleus basalis of Meynert (NBM), and reticular formation of the brainstem, but not in the locus coeruleus (LC), amygdala, or hippocampus.
Movement Disorders, Vol. 28, No. 6, 2013 - LB/a-syn
Pathophysiology
Animal model of Pink1
- moderate reduction in striatal DA levels accompanied by low locomotor activity, but do not exhibit major abnormalities in the DA neurons or striatal DA levels, and they do not show LB formation either
| Model / source | Note |
|---|---|
| PINK1 KO mice (Gispert, 2009 #942) |
- progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. - (In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and inspite of reduced expression of fission factor Mtp18,) we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons. - Reduced basal ATP level in Pink1 dissociated cells (A), reduction of basal Δψm in (B) dissociated cells and in (C) isolated mitochondria from Pink1 versus wildtype brain, as well as reduction of respiratory activities for complexes I+III+IV (Cx I) and IV (Cx IV) (D,E |
| (Kitada, 2007 #943) | numbers of dopaminergic neurons and levels of striatal dopamine (DA) and DA receptors are unchanged in PINK1/ mice. Amperometric recordings, however, revealed decreases in evoked DA release in striatal slices and reductions in the quantal size and release frequency of catecholamine in dissociated chromaffin cells. Intracellular recordings of striatal medium spiny neurons, the major dopaminergic target, showed specific impairments of corticostriatal long-term potentiation and long-term depression in |
| Alzforum |
- no reduction intyrosine hydroxylase immunolabeling no reduction intyrosine hydroxylase immunolabeling (Kelm-Nelson et al., 2018). - Moreover, dendritic health appears to be affected in PINK1 KO mice. The dendrites of midbrain dopaminergic neurons from 10-month-old KOs were shorter than those of wild-type mice. Also, the dendrites of cultured cortical neurons isolated from embryonic mice grew more slowly, and harbored shorter mitochondria that occupied less dendritic volume and traveled less distance anterogradely. These alterations were accompanied by deficits in mitochondrial protein kinase A signaling, as suggested by reduced phosphorylation of the enzyme's regulatory subunit β (DasBanerjee et al., 2017). - Cytokine levels in PINK1 KO mice serum were similar to those in wild-type mice, a surprising finding given the role PINK1 plays in mitophagy which, by removing damaged mitochondria, mitigates inflammatory responses. However, following exhaustive exercise, which acutely stresses mitochondria, cytokine concentrations shot up in the serum of KO, but not wild-type, mice (Sliter et al., 2018). - Altered shape, density, and movement of dendritic mitochondria were observed in cultured primary neurons from embryonic mice. |
입표: Genes associated with YOPD PD, (total 16, 이중 4 mt, 3 lysosome, 2 ubiquitination)
| locus | gene | protein | frequency* family Hx + & - combined | inheritance+ |
|---|---|---|---|---|
| Park2 | PARK2 | Parkin | 8.6% | AR |
| Park6 | PINK1 | Pten-induced putative kinase 1 | 3.7% | AR |
| Park1/4 | SNCA | α-syn | <1% | AD |
| Park8 | LRRK2 | Leucine-rich repeat kinase 2 (LRRK2) | <1% | AD |
| Park7 | PARK7 | DJ-1 (a mitochondrial protein) | <1% | AR |
| Park9 | ATP13A2 | Lysosomal type 5 ATPase | <1% | AR |
| Park3 | Unknown | Unknown | AD | |
| Park5 | UCHL1 | Ubiquitin c terminal hydrolase | AD | |
| Park11 | GIGYF2 | GRB interacting GYF protein 2 (involved in tyrosine kinase receptor signaling, and a repressor of translation initiation) | AD | |
| Park12 | Unknown | Unknown | X-linked | |
| Park13 | HTRA2 | HTRA serine peptidase 2 (a mt regulator) | AD | |
| Park14 | PLA2G6 | Phospholipase A2 (a subclass of enzyme that catalyzes the release of fatty acids from phospholipids.[8] This type of enzyme is responsible for breaking down (metabolizing) phospholipids.) | AR | |
| Park15 | FBX07 | F-box only protein 7 (involved in phosphorylation-dependent ubiquitination.) | AR | |
| Park17 | VPS35 | Vacuolar protein sorting 35 (involved in autophagy) | AD | |
| Park18 | EIF4G1 | Eukaryotic translation initiation factor 4 gamma 1 (involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure, and recruitment of mRNA to the ribosome.) | AD | |
| Park19 | DNAJC16 (auxilin) | DNAJ/HSP40 homolog (involved in regulate molecular chaperone activity by stimulating ATPase activity.) | AR |
Genes associated with late onset PD
| locus | gene | protein | frequency | OR |
|---|---|---|---|---|
| GBA | GBA | 2.3-9.4% | ~5 | |
| Park8 | LRRK2 | Leucine-rich repeat kinase 2 | Around 1% | 2.2 |
| TMEM175 | Transmembrane Protein 175 | 1.37 (p.393T) (Chang et al. 2017, PMID 28892059) | ||
| Park1/4 | SNCA | α-syn | <1% | 1.2-1.4 |
| Park6 | PINK1 | PINK1일부는 Late onset PD 도 연관있다는데?(Kasten, 2018 #708) |
- Frequency in familial PD cohorts (Kilarski et al., 2012, Bras et al., 2008, Djarmati et al., 2009) Table 1-1 Genes associated with familial PD and sporadic PD. Adapted from Hernandez et al.(2016), Kilarski et al. (2012), and Sidransky et al. (2009b) 표자체는 (Coppedè, 2012 #776(여기는 frequency x)
α-Synuclein and Lewy pathology in Parkinson’s disease – Kalia and Kalia
Table 1. Relationships between genetic forms of Parkinson’s disease and Lewy pathology
| gene | protein | protein present within Lewy bodies | Lewy bodies associated with disease |
|---|---|---|---|
| Monogenic Parkinson's disease | |||
| Autosomal dominant | |||
| SNCA | αSynuclein | + | + |
| LRRK2 | Leucine-rich repeat kinase 2 | + | +/- |
| VPS35 | Vocuolar protein sorting 35 | - | ? |
| EIF4G1 | Eukaryotic translation initiation foctor 4γ 1 | +/- | + |
| DNAJC13 | Receptor-mediated endocytosis 8 (REM-8) | +/- | + |
| CHCHD2 | Coiled-coil-helix-coiled-coil helix domain containing 2 | ? | ? |
| Autosomal recessive | |||
| Parkin | Parkin | + | +/- |
| PINK1 | PTEN-induced putative kinase 1 | + | + |
| DJ-1 | DJ-1 | + | ? |
| Other genetic parkinsonism | |||
| Autosomal dominant | ? | + | |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| top continuation | nonsense mutations in 14% | page begins mid-section; preceding bullet context is not visible in this photo. |
| Kilarski UK cohort line | UK Cohort: 136명의 EOPD 0. | the line ends with a trailing 0. whose meaning is unclear (likely an incomplete number or sentence). |
| Kilarski P value | P ¼ .01 and P < 1 10_4 | the visible glyphs include unusual spacing/characters; likely intended P = .01 and P < 1 × 10⁻⁴. |
| Kasten line | 83% is homoz, 17% is compound heteroz ( | the line ends with an open parenthesis; the parenthetical content is not visible in this photo. |
| Protein location | mitochondrial intermembrane space and membrane,^ | a small caret/footnote glyph appears after membrane,; preserved as visible source. |
| Animal model / Gispert row | trailing (D,E | the row’s final parenthesis is cut at the photo edge; the citation reference may continue. |
| Lewy pathology table | bottom Other genetic parkinsonism / Autosomal dominant row | the table is cut at the photo edge; only the heading and an empty ? / + cell pair are visible. |