Intrinsic link between PGRN and Gba1 D409V mutation dosage in potentiating Gaucher disease

Yi Lin ¹, Xiangli Zhao ², Benjamin Liou ¹

⁰Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, United States.

Human Molecular Genetics +

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August 5, 2024

View abstract on PubMed

Summary

Progranulin deficiency exacerbates Gaucher disease (GD) severity by impairing glucocerebrosidase (GCase) function. Higher GBA1 D409V mutation dosage in progranulin-deficient mice leads to increased neuroinflammation and neurodegeneration in GD.

Area Of Science

Neuroscience
Genetics
Biochemistry

Background

Gaucher disease (GD) stems from defective glucocerebrosidase (GCase) due to GBA1 mutations.
Progranulin (PGRN) is a known modifier of GCase, but its precise role in GD pathogenesis alongside GBA1 mutations is not fully understood.

Purpose Of The Study

To investigate the interplay between PGRN deficiency and GBA1 D409V mutation dosage on Gaucher disease severity.
To elucidate the molecular mechanisms underlying neuroinflammation and neurodegeneration in this context.

Main Methods

Development of mouse models with varying GBA1 D409V mutation dosages in a progranulin-deficient background (Grn-/-).
Comprehensive characterization using biochemical, pathological, transcriptomic, and neurobehavioral analyses.
Assessment of glycosphingolipid accumulation, lysosomal-autophagy dysfunction, microgliosis, and alpha-synuclein levels.

Main Results

Progranulin deficiency significantly worsened GD phenotypes, including earlier onset, reduced lifespan, and increased neurodegeneration.
Higher GBA1 D409V mutation dosage (hemizygous or homozygous) in progranulin-deficient mice led to profound inflammation and neurodegeneration.
Transcriptomic analysis revealed a strong correlation between GBA1 D409V dosage, PGRN loss, and altered gene expression related to lysosome dysfunction and neuroinflammation.

Conclusions

Disease severity in Gaucher disease is dependent on a threshold of GCase activity influenced by GBA1 D409V mutation dosage and progranulin deficiency.
These findings reveal critical underlying mechanisms of GD pathogenesis, highlighting the interplay between PGRN and GBA1 mutations.
This study provides insights into GBA1-associated neurodegenerative diseases.

Keywords:

Gaucher disease glucocerebrosidase mouse models neurodegeneration progranulin

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