Evidence map›Paper›PMID 40882878›Full record

ArticleNeurobiology of disease2025

A pathogenic alpha synuclein variant exacerbates disease progression in a neuron-specific Gba-KO mouse.

Hannah B D Duffy, Colleen Byrnes, Hongling Zhu, Y Terry Lee, Samantha Olmsted, Galina Tuymetova, Sydney N Pettit, Frances M Platt, Richard L Proia

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neurobiology of disease, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

Hannah B D DuffyGenetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
Colleen ByrnesGenetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Hongling ZhuMedical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Y Terry LeeGenetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Samantha OlmstedGenetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Galina TuymetovaGenetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Sydney N PettitGenetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Frances M PlattDepartment of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
Richard L ProiaGenetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: proia@nih.gov.

Funding

Translational Science Laboratory Shared ResourceP30CA138313 · NCI · MEDICAL UNIVERSITY OF SOUTH CAROLINA · PI Jian Ouyang · 2009 to 2026
$42.7M
RESEARCH PILOT PROJECTS PROGRAMP30GM103339 · NIGMS · MEDICAL UNIVERSITY OF SOUTH CAROLINA · PI OGRETMEN, BESIM · 2012 to 2016
$5.4M
Sphingolipid Biology of NeurodegenerationZ01DK056016 · NIDDK · NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES · PI PROIA, RICHARD · 2007 to 2008
$666k
Sphingolipid Biology And DiseaseZ01DK056000 · NIDDK · DIABETES, DIGESTIVE, KIDNEY DISEASES · PI PROIA, RICHARD L. · 1999 to 2006
–
Intramural NIH HHS Z01 DK056000Intramural NIH HHS Z01 DK056016NCI NIH HHS P30 CA138313NIGMS NIH HHS P30 GM103339
6 · The paper itself

Abstract

GBA variants are among the most significant genetic risk factors for synucleinopathies including Parkinson's disease and dementia with Lewy bodies. The GBA gene encodes the lysosomal enzyme glucocerebrosidase (GBA), which is essential for glycosphingolipid catabolism. There is a reciprocal relationship between GBA and α-synuclein (α-syn), in which reduced GBA levels lead to elevated α-syn. To further explore this connection specifically within neurons in vivo, we have introduced a human pathogenic variant of α-syn, A53T, into a neuron-specific Gba-KO mouse. This double variant mouse exhibited a reduced lifespan and more pronounced weight loss relative to the neuron-specific Gba-KO mouse, demonstrating a faster disease course and more severe phenotype. Additionally, their brains showed elevated levels of glucosylceramide and phosphorylated α-syn, while glucosylsphingosine levels were unchanged. Pathogenic α-syn had a greater effect on lifespan when combined with the neuron-specific Gba-KO than with KOs in Hexa or Hexb, genes linked to Tay-Sachs and Sandhoff disease, respectively. This model reveals that pathogenic α-syn amplifies GBA-related disease mechanisms within neurons, leading to an earlier and more severe disease course than with deficiencies in other glycosphingolipid-degrading enzymes.

Indexed as

alpha-SynucleinGlucosylceramidaseNeuronsSynucleinopathiesAnimalsBrainDisease Models, AnimalDisease ProgressionHumansMaleMiceMice, Inbred C57BLMice, Knockoutalpha-SynucleinGlucosylceramidaseAlpha synucleinGaucher diseaseGlucocerebrosidaseGlucosylceramideGlucosylsphingosineParkinson's diseaseSynucleinopathy

Identifiers

PMID40882878
PMCPMC13439556

What OpenQuestion holds

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LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.