TM for aSyn programs continued (TAK-341 in hippo / SNCA MEDI-1341 / SNCA p3 / How long?), Turnover of αSyn (Stefano 2018 #770 review with αSyn 240h half-life table by macroautophagy / cathepsin D / lysosomal pathways), ATP13A2 (Park9) opener (gene/structure, KRD, NCL, Heterozygous carriers, ATP13A2 in Lewy bodies)
TM for aSyn programs (continued)
| content | |
|---|---|
| 1 spreading? | TAK-341 in hippo → ↓ Syn-1 in ipsi hippocampus axons; cortex; hippo etc; cortex effects 외 보였다 한 이 hippocampus PD vs HC vs HC patient 가 1 1 (mode based on different mode of effect cell to cell) |
| IORxhino 20231 | (?) A second form of neuronal-derived PD derived from multiplications of the SNCA gene aSyn overexpression of WT αsyn has been characterized. These patients express however CNV resistance is impaired. Triplication appears to be fully penetrant, but duplications give a more variable presentation. Carriers identified are symptomatic 4 of 8 (NRT-2018 #2415, 11/16) |
| reduction of αsyn expression could significantly reduce risk | |
| SNCA / MEDI-1341 | [~50% only] αSyn spreading consequences in NHP suggesting both (Pansson 2018 #275; LION rxs); MEDI-1341 in NRT FUR is at 1 (3 fixed); Methods (Atuka 4-As; SnYn IFI 거 ?-FFR 일감); patient postmortem paper i 1.7 H-Y 5 characterization 1 ↑ Pa-Pi-1; ↑ 80-83 a 8 14 Loss of motor symptoms; 1 Loss neurodegeneration 1 도 ↑ 그 와 동시 화); DA characterization (cf 외 동물 OS / EM / Imaging) |
| SNCA p3 | study with adverse on tonsil afterm fines free RNA, lcms, CDMS, NFL ever boy Age-associated cumulative onset motor symptoms No defects? CDMS, NFL ever boy SNCA WT αSyn duplication CNV5 65978 256 vs triplication CNV9 25596 33 Aage 4-As 6.6.5 |
| How long? | what percentage of αSyn is present in the extracellular space and how much is accessible to an antibody as α-syn tends to bind other proteins which may shelter the epitopes being How do we look after pathology and progression of neuropathology in clinical symptoms? when do we look quickly we look more imperatively if where a ‘point of no return’ of αSyn pathology has been reached |
Turnover of αSyn
Below table many from (Stefano, 2018 #770)‘s review (le Indery citing)
- (Saxisi, 2010) Human αsyn: turnover (1) in plasma and brain were assumed to be similar and equal to 10 days (240 h) based on measurements of αSyn in CSF after in vivo metabolic labeling with heavy water (2010); (Yamara et al. 2012)
- Human αSyn has a half life of 87 hr; A537 mutation is the same (Murata, 2014 #100)
- Wild-type mouse DCA degradation (1486) is substantially slower than that of human DCA (Fishbein, 2014)
In the absence of α-syn turnover of the mouse DCA proteins of being 1.5 days. Notably in the mouse DCA proteins are present in the human DCA mutation. Thus from an evolutionary perspective stressed reasoning that the mature murine short the upon makes Asian beaver to mate AS a 537 the appropriate of pathways and thus a longer half life for DCA could be tolerated to a mature low.
| α-syn species | degradation pathway / enzyme | findings |
|---|---|---|
| Soluble monomer / Oligomeric αSyn | CMA | (Sussman 2007 #1731), CMA (Allendorfer-Gonzalez 2018 #2601). Old CMA cannot degrade α-syn aggregates form microautophagy → recognized by HSC70 → translocation directly into the lysosomes via interaction with LAMP2A → degradation by Cathepsin D, B, L |
| Macroautophagy LIPS both 205 and 26S proteasomes degrade αSyn in purified system | Cathepsin D — Cathepsin KO mice show preferential accumulation of α-Syn oligomers & aggregates; similar findings were reported in human brains deficient in cathepsin D (Bae 2015 #775); CTSD haploinsufficiency 1 ↑ accumulation of internalized αsyn aggregates and the secretion of the aggregates | |
| Internalized αSyn | MGS deg cells of αSyn | is degraded in part by macroautophagy. Cathepsin D — (Bae 2015 #775) CTSD haploinsufficiency 1 ↑ accumulation of internalized α-syn aggregates |
| axonal/synaptic αSyn pS129 monomer / pS129 monomer αSyn / aggregated αSyn | UPS (with lysosome doing complementary role); Primarily UPS; Not degraded | |
| extracellular proteolytic enzymes | Degraded by | |
| Taken up by microglia through (particularly) microglial receptors (TLR2 and β-1 integrin and astrocyte) | Degraded by lysosomes — stimulate TLR2 inflammation pathway | |
| Taken up by neurons | Degraded by lysosomes | (Kim, 2008 #2728) Degradation of endocytosed α-syn fibrils by the lysosomal pathway. Endocytosis and lysosomal-dependent degradation of extracellular α-syn. We found that the internalized monomers were removed from cells very rapidly with a half-life of <2 min. |
| αSyn fibril | (Schedlich, 2017 #275): taken up by (F-actin-dependent) intracellular nanotube (formed with neurons) → transfer αsyn to neighboring microglia → αSyn degraded in the microglia |
ATP13A2 (Park9)
The ATP13A2 gene encodes a transmembrane lysosomal P5-type ATPase (ATP13A2) (Dahay et al., 2010); (Fernandez, 2020 #1296) upregulated in single-cell transcriptomics (DAT n)
introduction:
- Loss of divalent metal cations as well as polyamines (eg spermine) on lysosomal membranes
- In 2020 Nature paper, it was discovered that ATP13A2 transports polyamines from lysosome to cytosol, whereas mutations in the ATP13A2 gene causes polyamine accumulation in lysosome. The lysosomal polyamine accumulation causes lysosomal dysfunction.
- ATP13A2 deficiency also reduces cytosolic polyamine (which is known to have antioxidant properties), leading to higher ROS accumulation. Consistent with these results, multiple papers showed ATP13A2 overexpression rescues cell survival and recovers mitochondria and lysosome dysfunction.
- (Anderson, 2021) Studies with PD patient-derived mutant ATP13A2 fibroblasts and ATP13A2 knockdown DA neurons have shown that PD-linked mutations in ATP13A2 lead to several lysosomal alterations, including impaired lysosomal acidification, decreased activity of lysosomal enzymes, reduced degradation of lysosomal substrates and defective clearance of autophagosomes (129)
- ATP13A2 deficiency and mutation have also been shown to cause the reduction in the level of cathepsin D.
- PD ATP13A2 deficient cells:
- over-expression of wild-type ATP13A2 in ATP13A2-deficient cells restores lysosomal function and prevents cell death (125)
- over-expression of wild-type ATP13A2 in α-syn-stable HEK293T cell lines reduced intracellular α-syn levels and instead promoted intracellular accumulation of α-syn at the secretion of α-syn (130)
- Over-expression of ATP13A2 rescued DA neuron degeneration caused by overexpressed α-syn in rat primary midbrain cultures and in C. elegans (131)
NCL
- a single homozygous missense mutation in PARK9 (M810R) has been reported leading to onset of Neuronal Ceroid Lipofuscinosis (NCL) in humans 86
- PARK9-associated NCL initially presents with learning difficulties in childhood. Progress in cognitive and motor decline.
Kufor-Rakeb disease (KRD)
- The loss-of-function mutations in the ATP13A2 gene cause an autosomal recessive form of Parkinsonism known as the Kufor-Rakeb disease (KRD) (Williams et al., 2005)
- Cf form of FD: KRD typically appears in early adulthood and shows a number of symptoms in addition to characteristic features, including supranuclear gaze palsy, oculogyric dystonic spasms, facial and finger mini myoclonus, and visual hallucinations (Williams et al. 2005). It is achieved that this disease is mediated by lysosomal dysfunction, probably resulting from disrupted protein aggregation (Ramirez et al., 2006)
- In humans, neurogenesis, dendrite extensions and splice site mutations in functionally important domains of the protein have been identified (89), KRD which typically manifests in adolescence or young adulthood is characterized by Parkinsonian motor signs (tremor bradykinesia rigidity) in association with spasticity, supranuclear gaze palsy and dementia. Pathological features in KRD have been described as widely studies have not been reported in detail.
PD
- Heterozygous carriers of PARK9 mutations have been reported with increased PD risk in some (90-93) but not all (94, 95) studies. ATP13A2 levels are decreased in dopaminergic nigral neurons from sporadic PD patients (data not shown) (Dehay, 2012 #1771); we identified ATP13A2 as a component of Lewy bodies; in particular ATP13A2 is located in the core of Lewy bodies where it is surrounded by more peripherally located SNCA (data not shown) (Dehay, 2012 #1771)
- A separate study demonstrated… ATP13A2 contains an auto-inhibitory domain that can be targeted for activation for the compound. HTS seems feasible by conducting a cell-free ATPase assay using purified ATP13A2.