TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia
Nicholson AM, Finch NA, Wojtas A, Baker MC, Perkerson RB, Castanedes-Casey M, Rousseau L, Benussi L et al.. Journal of neurochemistry, 2013-07-01
Topic: Brain proteins, microglia and lab models
Frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLD-TDP). Recently, a genome-wide association study identified the first FTLD-TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD-TDP risk. Intriguingly, the most significant association was in FTLD-TDP patients carrying progranulin (GRN) mutations. Here, we investigated to what extent the coding variant, rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and transmembrane protein 106 B (TMEM106B) regulation. First, we confirmed the association of TMEM106B variants with FTLD-TDP in a new cohort of GRN mutation carriers. We next generated and characterized a TMEM106B-specific antibody for investigation of this protein. Enzyme-linked immunoassay analysis of progranulin protein levels showed similar effects upon T185 and S185 TMEM106B over-expression. However, over-expression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N-glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD-TDP risk. We studied the p.T185S TMEM106B genetic variant previously implicated in frontotemporal dementia with TAR DNA binding protein 43 pathology caused by progranulin mutations. Our cell culture studies provide evidence that the protective S185 isoform is degraded more rapidly than T185 TMEM106B, potentially due to differences in glycosylation. These findings suggest that low TMEM106B levels might protect against FTLD-TDP in these patients.
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APA 7th
Nicholson, A. M., Finch, N. A., Wojtas, A., Baker, M. C., Perkerson, R. B., Castanedes-Casey, M., et al. (2013). TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia. Journal of neurochemistry. https://doi.org/10.1111/jnc.12329
Vancouver
Nicholson AM, Finch NA, Wojtas A, Baker MC, Perkerson RB, Castanedes-Casey M, et al. TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia. Journal of neurochemistry. 2013. doi:10.1111/jnc.12329. PMID: 23742080.
BibTeX
@article{nicholson2013-23742080,
author = {Nicholson, A. M. and Finch, N. A. and Wojtas, A. and Baker, M. C. and Perkerson, R. B. and Castanedes-Casey, M. and Rousseau, L. and Benussi, L. and others},
title = {{TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia}},
journal = {Journal of neurochemistry},
year = {2013},
doi = {10.1111/jnc.12329},
pmid = {23742080},
url = {https://doi.org/10.1111/jnc.12329}
}
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Key findings
- Recently, a genome-wide association study identified the first FTLD-TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD-TDP risk.
- Intriguingly, the most significant association was in FTLD-TDP patients carrying progranulin (GRN) mutations.
- Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N-glycosylation at residue N183.
- Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD-TDP risk.
- These findings suggest that low TMEM106B levels might protect against FTLD-TDP in these patients.
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Study details
- Evidence strengthModerate
How this study scored 40/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 23 of the 58 points we could judge it on, which is 40 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of neurochemistry) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2013 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 23742080) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 23 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 23 of the 58 points we could judge it on is 40 out of 100. |
| Total | 40 / 100 | — |
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