Two Lysosomal Genes ATP13A2 and GBA1 Interact To Drive Neurodegeneration

Authors

• Mingxue Gu
• Jinghan Zhao
• Mingxi Deng
• Guang Lin
• Xueyang Pan
• Wenwen Lin
• Mengqi Ma
• Jinyong Kim
• Seul Kee Byeon
• Akhilesh Pandey
• Lara M Lange
• Chad A Shaw
• Jonggeol Kim
• Joanne Trinh
• Christine Klein
• Oguz Kanca
• Joshua M Shulman
• Hugo J Bellen

Publication Date

1-30-2026

Journal

Molecular Neurodegeneration

DOI

10.1186/s13024-025-00923-z

PMID

41618357

PMCID

PMC13001375

PubMedCentral® Posted Date

1-30-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Background: Parkinson’s disease (PD) is a genetically complex disorder in which combinations of heterozygous risk variants may contribute to pathogenesis. Many PD risk loci encode lysosomal genes, such as GBA1, a common and potent risk factor, conferring at least a 5-fold increase. However, the mechanisms of GBA1 penetrance remain poorly understood.

Methods: Using Drosophila melanogaster, we performed a genetic interaction screen of lysosomal storage disorder (LSD) genes to identify dominant modifiers of Gba1b (fly homolog of GBA1). Age-dependent locomotor assessments, electroretinograms (ERG), transmission electron microscopy (TEM) analyses and quantification of dopaminergic (DA) neurons were used to assess the neurodegenerative phenotypes of double heterozygous animals. By combining immunostaining, lipidomics, metabolomics and pharmacological approaches we showed how partial loss of anne (fly homolog of ATP13A2) and Gba1b drives neurodegeneration. By interrogating genetic data from local and international PD cohorts we identified double heterozygous pathogenic variants in ATP13A2 and GBA1 in individuals with PD.

Results: We show that anne is expressed in neurons, whereas Gba1b is expressed in glia. Flies heterozygous for anne exhibit mild neurodegenerative phenotypes, and Gba1b strongly enhances this haploinsufficiency. Double heterozygous (Gba1bT2A/+;anneT2A/+) flies exhibit a slow and progressive neurodegeneration associated with accumulation and impaired acidification of lysosomes in photoreceptors and other neurons. Obvious morphological defects are first observed in glia at day 15 after eclosion and include vacuolization and neuronal detachment. These defects are accompanied by an elevation of glucosylceramide (GlcCer) and followed by loss of neuronal function and degenerative features by day 30. These phenotypes are neuronal activity-dependent. The neurodegenerative phenotypes are rescued by: ML-SA1, an agonist of the lysosomal TRPML1 channel that has been reported to promote lysosomal membrane trafficking; myriocin, a compound that inhibits GlcCer production; and DFMO, a drug which inhibits polyamine synthesis. Based on surveys of genetic data, we identify multiple PD cases harboring digenic variants in GBA1 and ATP13A2.

Conclusions: Our study reveals that partial loss of Gba1b in glia and anne in neurons synergistically disrupts lysosomal pH and neuron-glia GlcCer homeostasis, triggering neurodegeneration. Our results provide evidence that GBA1 penetrance is influenced by additional genetic modifiers, consistent with a putative digenic mechanism for GBA1-PD penetrance. These findings highlight lysosomal acidification, sphingolipid clearance, and polyamine regulation as critical intervention points in digenic PD.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13024-025-00923-z.

Keywords

Parkinson’s disease, Lysosomal dysfunction, Elevated glucosylceramide, Glial dysfunction

Published Open-Access

yes

Recommended Citation

Gu, Mingxue; Zhao, Jinghan; Deng, Mingxi; et al., "Two Lysosomal Genes ATP13A2 and GBA1 Interact To Drive Neurodegeneration" (2026). Duncan NRI Faculty and Staff Publications. 197.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/197