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Multi-omics insights into GBA1-associated Parkinson’s disease: interplay of genomics, transcriptomics, proteomics, and lipidomics

Year: 2026

Type: article

Abstract: Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide. The pathogenesis of PD is driven by multifactorial mechanisms involving a complex interplay among environmental exposures, genetic susceptibility, and aging-related processes. Among genetic contributors, heterozygous pathogenic variants in the GBA1 gene represent the most significant heritable risk factor for PD. The disease mechanisms of GBA1 defects in PD remains incompletely understood. It has been proposed that a partial loss-of-function of the lysosomal enzyme glucocerebrosidase, or potential toxic gain-of-function effects (e.g., endoplasmic reticulum stress) might contribute to the disease. These processes initiate a cascade of pathophysiological events, including dysregulated sphingolipid metabolism, compromised lysosomal-autophagic function, mitochondrial dysfunction, and accelerated α-synuclein aggregation. Subsequent dopaminergic neurodegeneration and sustained neuroinflammatory cascades ultimately drive PD progression. Nevertheless, the precise molecular mechanisms linking GBA1 mutations to PD pathogenesis remain incompletely elucidated, and clinically validated early diagnostic biomarkers for GBA1-associated PD (GBA1-PD) are still lacking. This review summarizes the distinct clinical phenotypes and mechanistic underpinnings of GBA1-PD, with particular emphasis on omics-derived stratification biomarkers (identified through genomics, transcriptomics, proteomics, and lipidomics approaches) coupled with neuroimaging signatures. This review advances our understanding of GBA1-mediated PD pathogenesis while providing a framework for developing precision diagnostic strategies and targeted therapeutic interventions addressing PD heterogeneity.

Source: Molecular Neurodegeneration

DOI: 10.1186/s13024-026-00931-7

Authors: Yang Ni, Huaibin Cai, Yaping Shao, Weidong Le

Institutions: Dalian Medical University, First Affiliated Hospital of Dalian Medical University, National Institutes of Health, National Institute on Aging, Shanghai University of Medicine and Health Sciences

Language: English

Topic: Lysosomal Storage Disorders Research

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,090