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

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 -synuclein ( -syn), in which reduced GBA levels lead to elevated -syn. To explore this relationship specifically within neurons in vivo, we have introduced a human pathogenic variant of -syn, A53T, into a neuron-specific Gba-KO mouse. This double variant mouse exhibited a reduced lifespan relative to the neuron-specific Gba-KO mouse and more pronounced weight loss, demonstrating a faster disease course and more severe phenotype than neuron-specific Gba-KO mice. Additionally, their brains showed elevated levels of glucosylceramide (GlcCer) and phosphorylated -syn compared to the single-variant mice. Surprisingly, glucosylsphingosine (GlcSph) levels were comparable between double-variant and neuron-specific Gba-KO mice, suggesting impaired GlcSph generation. A small number of genes were significantly different between double variant and neuron-specific Gba-KO mice. These findings suggest that GlcCer accumulation, due to GBA loss, interacts with -syn in neurons, driving increased pathogenic -syn levels and modulating GlcCer metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE289837 | GEO | 2026/02/01

REPOSITORIES: GEO

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Project description:Phosphatase and Tensin Homolog (PTEN) is a dual-specific protein and lipid phosphatase that regulates AKT and downstream signaling of the mechanistic target of rapamycin (mTOR). PTEN functions as a tumor suppressor gene whose mutations result in PTEN Hamartoma Tumor Syndrome (PHTS) characterized by increased cancer risk and neurodevelopmental comorbidity. Here, we generated a novel neuron-specific Pten knock-out mouse model (Syn-Cre/Pten HOM) to test the ability of pharmacologic mTOR inhibition to rescue Pten mutation-associated disease phenotypes in vivo and in vitro. We found that treatment with the mTOR inhibitor, everolimus, increased the survival of Syn-Cre/Pten HOM mice while some neurologic phenotypes persisted. Transcriptomic analyses revealed that in contrast to mice harboring a neuron-specific deletion of the Tuberous Sclerosis Complex 2 gene (Syn-Cre/Tsc2 KO), genes that are under AKT regulation were significantly increased in the Syn-Cre/Pten HOM mice. In addition, genes associated with synapse, extracellular matrix, and myelination were broadly increased in Syn-Cre/Pten HOM mouse neocortex. These findings were confirmed by immunostaining of cortical sections in vivo, which revealed excessive immunoreactivity of myelin basic protein and perineuronal nets (PNN), the specialized extracellular matrix surrounding fast-spiking parvalbumin (PV) interneurons. We also detected increased expression of Synapsin I/PSD95 positive synapses and network hyperactivity phenotypes in Syn-Cre/Pten HOM mice neurons compared to wild-type (WT) neurons in vitro. Strikingly, everolimus treatment rescued the number of synapses and network hyperactivity in the Syn-Cre/Pten HOM mice cortical neuron cultures. Taken together, our results revealed in vivo and in vitro molecular and neuronal network mechanisms underlying neurological phenotypes of PHTS. Notably, pharmacologic mTOR inhibition by everolimus led to successful downstream signaling rescue, including mTOR complex 1 (mTORC1) site-specific suppression of S6 phosphorylation, correlating with phenotypic rescue found in our novel neuron-specific Syn-Cre/Pten HOM mice.

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

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