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Proteolytic processing of Neuregulin-1
Willem M.. Brain research bulletin, 2016-07-05
Topic: Disease mechanisms in lab and animal studies
Neuregulin-1 (NRG1), known also as heregulin, acetylcholine receptor inducing activity (ARIA), glial growth factor (GGF), or sensory and motor neuron derived factor (SMDF), is a key factor for many developmental processes and in adult brain. All known splice variants contain an epidermal growth factor (EGF)-like domain, which is mediating signaling via receptors of the ErbB family. In particular, NRG1 acts as an essential signaling molecule expressed on the axonal surface, where it signals to Schwann cells throughout development and regulates the thickness of the myelin sheath. NRG1 is required also by other cell types in the nervous system, for instance as an axonal signal released by proprioceptive afferents to induce development of the muscle spindle, and it controls aspects of cortical interneuron development as well as the formation of thalamo-cortical projections. The precursor protein of NRG1 can be activated and released from the membrane through limited proteolysis by the β-Secretase (β-site amyloid precursor protein cleaving enzyme 1, BACE1) which was first identified through its function as the rate limiting enzyme of amyloid-β-peptide (Aβ) production. Aβ is the major component of amyloid plaques in Alzheimer's disease (AD). Due to the hairpin nature of NRG1 type III two membrane-bound stubs with a type 1 and a type 2 orientation are generated by an initial proteolytic cleavage and successive release of the EGF-like domain either by dual cleavage by BACE1 or by ADAM17 (a disintegrin and metalloprotease) which is also called TACE (Tumor Necrosis Factor-α-converting enzyme). The cleavages activate NRG1 to allow juxtacrine or paracrine signaling. The type 1 oriented stub is further cleaved by γ-secretase in the transmembrane domain with a putative role in intracellular domain (ICD) signaling, while the type II oriented stub is cleaved by signal peptidase like proteases (SPPLs). Neuregulin-1 was identified as a major physiological substrate of BACE1 during early postnatal development when similarities in BACE1 KO mice and NRG1 heterozygous mice were discovered. Both display severe hypomyelination of peripheral nerves. Later it was shown with genetic and pharmacological evidence that the developmental effect of type I NRG1 on the formation and the maintenance of muscle spindles is BACE1 dependent. Thus, NRG1 functions in PNS and CNS are likely to set limits to an Alzheimer disease therapy with relatively strong BACE1 inhibition.
Key findings
- The type 1 oriented stub is further cleaved by γ-secretase in the transmembrane domain with a putative role in intracellular domain (ICD) signaling, while the type II oriented stub is cleaved by signal peptidase like proteases (SPPLs).
- Neuregulin-1 was identified as a major physiological substrate of BACE1 during early postnatal development when similarities in BACE1 KO mice and NRG1 heterozygous mice were discovered.
- Both display severe hypomyelination of peripheral nerves.
- Later it was shown with genetic and pharmacological evidence that the developmental effect of type I NRG1 on the formation and the maintenance of muscle spindles is BACE1 dependent.
- Thus, NRG1 functions in PNS and CNS are likely to set limits to an Alzheimer disease therapy with relatively strong BACE1 inhibition.
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Study details
- Evidence strengthLow
How this study scored 36/100
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 21 of the 58 points we could judge it on, which is 36 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Brain research bulletin) |
| 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 | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2016 — 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 27393467) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 21 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 21 of the 58 points we could judge it on is 36 out of 100. |
| Total | 36 / 100 | — |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Willem, M. (2016). Proteolytic processing of Neuregulin-1. Brain research bulletin. https://doi.org/10.1016/j.brainresbull.2016.07.003
Vancouver
Willem M. Proteolytic processing of Neuregulin-1. Brain research bulletin. 2016. doi:10.1016/j.brainresbull.2016.07.003. PMID: 27393467.
BibTeX
@article{willem2016-27393467,
author = {Willem, M.},
title = {{Proteolytic processing of Neuregulin-1}},
journal = {Brain research bulletin},
year = {2016},
doi = {10.1016/j.brainresbull.2016.07.003},
pmid = {27393467},
url = {https://doi.org/10.1016/j.brainresbull.2016.07.003}
}
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