UPS impairment tail, PTM wheel, Metabolomics/Omics, Cis-vs-Trans, Intracellular delivery
UPS impairment in PD patients (table tail)
| questions | |
| Positioning with other aSyn-targeting agents What are the levels of O-GlcNAcylation of these proteins (Altered level in PD and do they change during the progression of disease?) O-GlcNAc modification is highly abundant in the mammalian brain and neuron-specific proteins undergo O-GlcNAcylation Symptomatic drug (via synapse?) | |
| In AD | Reduced O-GlcNAcylation in AD brains |
Frequency
PTM wheel — Target Protein
- Amnio Acid Modification (Irreversible)
- Deamidation
- Eliminylation
- Cleavage (Irreversible)
- Proteolysis
- Reversible Addition Of Polypeptides
- Ubiquitylation
- UBL-protein Conjugation (e.g. SUMO)
- Addition Of Complex Molecules (Reversible)
- AMPylation
- ADP-Ribosylation
- Glycosylation
- Prenylation
- Addition Of Chemical Groups (Reversible)
- Hydroxylation
- Phosphorylation
- Acetylation
- Methylation
(All groups feed arrows into a central Target Protein.)
| Frequency | Modification |
|---|---|
| 58383 | Phosphorylation |
| 6751 | Acetylation |
| 5526 | N-linked glycosylation |
| 2844 | Amidation |
| 1619 | Hydroxylation |
| 1523 | Methylation |
| 1133 | O-linked glycosylation |
| 878 | Ubiquitylation |
| 826 | Pyrrolidone carboxylic acid |
| 504 | Sulfation |
Common PTMs by residue
Metabolomics
- Small molecule: 50 – 1500 daltons (Da). 이 대상
- Examples of metabolites: glucose, cholesterol, amino acid (보통 protein 은 안 다루네)
Omics
| Merit | caveat | How to overcome | ||
|---|---|---|---|---|
| Genomics | Only a small proportion of the genetic components of the disease | Ignore lipids and carbohydrates | ||
| A pathologic process is so downstream from genetics & transcriptomics | ||||
| Transcriptomics | A pathologic process is so downstream from genetics & transcriptomics | Ignore lipids and carbohydrates | ||
| Only 40% of the variation of protein concentration is explained by mRNA abundacy, an transcript expression levels for a specific transcript product may not correlate to its protein expression level. there may be quite large variations in transcript levels that are not reflected in similar changes in protein levels | ||||
| In (ONLY) large-scale expression analyses comparing differential expression for specified products at transcript and protein level, the major ity of the overall expression levels show a positive correlation (Nagaraj et al., 2011; Xu et al., 2012). | Don't capture post translational modifications (eg. GBA+PD has no change in mRNA LEVEL, eg. phosphorylation) | |||
| quantify most transcript types (coding & non-codng) present in a given sample | daily (circadian) clocks cause extensive transcriptomic and proteomic changes, | Site-directed transcriptomi… | ||
| Proteomics | Proteins directly operate in the cells and are therefore closer to the functional level. | quantitative proteomics can only measure the most abundant proteins present in this sample | Correlation with disease progression? | |
| daily (circadian) clocks cause extensive transcriptomic and proteomic changes, | ||||
| Metabolomics | Correlation with disease progression? |
Temporal & spatial
| Body fluids | Tissue-based Temporal & spatial aspect | ||
| Too dilute Temporarily removed Bind and grind |
Cis- vs Trans-
| cis | Trans | |
|---|---|---|
| 의 의미 | cis-acting (cis-regulatory) acting from the same molecule" (i.e., | trans-acting (trans-regulatory) acting from a different molecule |
| intramolecular | intermolecular | |
| gene level | Cis-acting elements:, do not code for protein or RNA. | The trans-acting gene (=trans-regulatory element) : may be on a different chromosome to the target gene, → encodes (trans-acting factors (ie often proteins such as transcription factors) or encodes) → modify the expression of distant genes. |
| the context of transcription regulation | a regulatory protein that binds to DNA. ('trans-acting factor' which binding to a cis-regulatory element in DNA) eg: micro RNAs |
Intracellular delivery
| over | ? | In vitro | In vivo | human | |
|---|---|---|---|---|---|
| AAV | |||||
| e | 'transfection' | ● DNA cannot enter cells. Plasmid (?) AAV | |||
| ein | 'transduction' | studied protein transduction domains (PTDs) are derived from the Drosophila homeotic transcription factor Antennapedia (Antp), the herpes simplex virus (HSV) protein VP22, and the human immunodeficiency virus (HIV)-1 transcriptional activator Tat | 2017 Bruce |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Intracellular delivery left column | e, ein, over, ? | reads as truncated tokens at the very left edge of the body; these are visible fragments of column headers/row labels (over is part of Delivery method, e of gene, ein of protein) cut by the page edge; preserved verbatim. |