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Glucocerebrosidase and Parkinson disease: Recent advances
Schapira AH.. Molecular and cellular neurosciences, 2015-03-20
Topic: Brain proteins, microglia and lab models
Mutations of the glucocerebrosidase (GBA) gene are the most important risk factor yet discovered for Parkinson disease (PD). Homozygous GBA mutations result in Gaucher disease (GD), a lysosomal storage disorder. Heterozygous mutations have not until recently been thought to be associated with any pathological process. However, it is clear that the presence of a GBA mutation in homozygous or heterozygous form is associated with an approximately 20-fold increase in the risk for PD, with little if any difference in risk burden related to gene dose. Most studies suggest that 5-10% of PD patients have GBA mutations, although this figure is greater in the Ashkenazi population and may be an underestimate overall if the entire exome is not sequenced. GBA-associated PD is clinically indistinguishable from idiopathic PD, except for slightly earlier age of onset and a greater frequency of cognitive impairment. Pathological and imaging features, and response to pharmacotherapy are identical to idiopathic PD. GBA mutations result in reduced enzyme activity and mutant protein may become trapped in the endoplasmic reticulum (ER) leading to unfolded protein response and ER associated degradation and stress. Both mechanisms may be relevant in GD and PD pathogenesis and lead to impaired lysosomal function. Of particular relevance to PD is the interaction of glucocerebrosidase enzyme (GCase) with alpha-synuclein (SNCA). There appears to be a bi-directional reciprocal relationship between GCase levels and those of SNCA. Thus reduced GCase in GBA mutation PD brain is associated with increased SNCA, and increased SNCA deposition is associated with reduced GCase even in GBA wild-type PD brains. It is noteworthy that GBA mutations are also associated with an increase in risk for dementia with Lewy bodies, another synucleinopathy. It has been suggested that the relationship between GCase and SNCA may be leveraged to reduce SNCA levels in PD by enhancing GCase levels and activity. This hypothesis has been confirmed in GBA mutant mice, PD patient fibroblasts and cells with SNCA overexpression, and offers an important target pathway for future neuroprotection therapy in PD. This article is part of a Special Issue entitled 'Neuronal Protein'.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Schapira, A. H. (2015). Glucocerebrosidase and Parkinson disease: Recent advances. Molecular and cellular neurosciences. https://doi.org/10.1016/j.mcn.2015.03.013
Vancouver
Schapira AH. Glucocerebrosidase and Parkinson disease: Recent advances. Molecular and cellular neurosciences. 2015. doi:10.1016/j.mcn.2015.03.013. PMID: 25802027.
BibTeX
@article{schapira2015-25802027,
author = {Schapira, A. H.},
title = {{Glucocerebrosidase and Parkinson disease: Recent advances}},
journal = {Molecular and cellular neurosciences},
year = {2015},
doi = {10.1016/j.mcn.2015.03.013},
pmid = {25802027},
url = {https://doi.org/10.1016/j.mcn.2015.03.013}
}
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.
Key findings
- Homozygous GBA mutations result in Gaucher disease (GD), a lysosomal storage disorder.
- Heterozygous mutations have not until recently been thought to be associated with any pathological process.
- However, it is clear that the presence of a GBA mutation in homozygous or heterozygous form is associated with an approximately 20-fold increase in the risk for PD, with little if any difference in risk burden related to gene dose.
- Most studies suggest that 5-10% of PD patients have GBA mutations, although this figure is greater in the Ashkenazi population and may be an underestimate overall if the entire exome is not sequenced.
- GBA mutations result in reduced enzyme activity and mutant protein may become trapped in the endoplasmic reticulum (ER) leading to unfolded protein response and ER associated degradation and stress.
Why it matters
This review reports that GBA mutations in homozygous or heterozygous form are associated with an approximately 20-fold increase in Parkinson disease risk, and that GBA-associated Parkinson disease is clinically indistinguishable from idiopathic Parkinson disease except for slightly earlier onset and more frequent cognitive impairment. It describes mechanisms including reduced enzyme activity and mutant protein trapped in the endoplasmic reticulum leading to impaired lysosomal function.
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Study details
- Evidence strengthLow
How this study scored 45/100
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, so that was left out: it earned 43 of the 96 points we could judge it on, which is 45 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular and cellular neurosciences) |
| 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 | 2015 — 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 | 5 / 7 | Cited 220 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 16.9 citations a year over 13 year(s) since 2015 |
| Impact for its field and year | 4 / 6 | Cited 19.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 2 / 4 | Cited 25 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Anthony H.V. Schapira: h-index 129 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 25802027) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 43 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 43 of the 96 points we could judge it on is 45 out of 100. |
| Total | 45 / 100 | — |
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