Objective: The work presented here aims to link the lipidome changes leading to functional defects, and eventual cell death, in GBA1 mutant dopaminergic neurons derived from Parkinson’s disease patients.
Background: Parkinson’s disease (PD) is second most prevalent neurodegenerative disorder, characterized by the progressive loss of motor function attributed to a depletion of dopaminergic neurons in the substantia nigra pars compacta. The disease’s trajectory is marked by the accumulation of alpha-synuclein insoluble aggregates and lysosomal impairment.
Mutations in the lipid hydrolase gene GBA1 emerge as a primary genetic risk factor, conferring a 15% increased risk compared to the general population. Such mutations result in enzyme loss of function, culminating in the accumulation of lipid substrates. GBA1 depletion is discernible even in PD patients lacking genetic mutations, strengthening the association between lipid accumulation and PD development. This study extensively characterizes the functional, morphological, and lipidomic features in dopaminergic neurons derived from PD patients’ induced pluripotent stem cells (iPSCs) with and without GBA1 mutations.
Method: A high content screening (HCS) approach was set up to quantify lysosomal markers, alpha-synuclein aggregates, and neuronal network morphology. The same workflow was used to monitor calcium signalling and to record electrophysiological activity. A cutting-edge mass-spectrometry technique was used to profile dopaminergic neurons lipidome.
Results: Our findings unveil a distinctive lipidome signature in dopaminergic neurons with GBA1 mutations, characterised by an accumulation of sphingolipids and phospholipids, along with a reduction of carnitine levels. At the same time a noteworthy accumulation of alpha-synuclein aggregates and phosphorylated forms of synuclein, and reduction of lysosomal markers was detected. Moreover, the conducted functional analysis exposes that lipid and alpha-synuclein accumulation precipitates functional defects, evidenced by impaired calcium signalling and neuronal network dysfunction.
Conclusion: These revelations mark a pioneering report on the effects of GBA1 mutations at omics and functional levels, paving the way for the identification of a multi-targeted pharmacological approach to PD. The insights presented here offer a significant basis toward understanding the intricate interplay of genetic and molecular factors contributing to PD.
To cite this abstract in AMA style:
G. Uras, S. Lucas-Del-Pozo, F. Fierli, S. Koletsi, V. Lentini, P. Caboni, C. Manis, D. Di Lisa, A. Andolfi, L. Pastorino, A. Schapira. The functional and lipidome signature of GBA1 mutant dopaminergic neurons [abstract]. Mov Disord. 2024; 39 (suppl 1). https://www.mdsabstracts.org/abstract/the-functional-and-lipidome-signature-of-gba1-mutant-dopaminergic-neurons/. Accessed October 4, 2024.« Back to 2024 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/the-functional-and-lipidome-signature-of-gba1-mutant-dopaminergic-neurons/