MassIVE MSV000097594

Complete Public PXD062821

Pingping_2025_NC_N-acetyl-l-leucine_PD

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Description

Abstract N-acetyl-L-leucine (NALL), a derivative of the branched-chain amino acid leucine, has shown therapeutic potential in neurodegenerative diseases, including in prodromal stages of Parkinson s disease (PD). However, the mechanism of its protective effects has been largely unknown. Using discovery-based proteomics, we found that treatment with NALL led to upregulation of lysosomal, mitochondrial, and synaptic proteins in PD patient-derived dopaminergic neurons. NALL reduced levels of pathological pS129-alpha-synuclein in dopaminergic neurons from patients harboring GBA1 or LRRK2 mutations. This decrease in pS129-syn was dependent on serine protease HTRA1 that was induced by NALL treatment of dopaminergic neurons. NALL also upregulated expression of wild-type parkin in both GBA1 and LRRK2 mutant neurons, leading to an increase in functional dopamine transporter and synaptic membrane-associated synaptojanin-1, suggesting improved synaptic function. Furthermore, NALL treatment of mutant LRRK2R1441C knock-in mice led to decreased pS129-alpha-synuclein, increased parkin and improved dopamine-dependent motor learning deficits. These findings highlight the therapeutic potential of NALL in PD by its protective effects on alpha-synuclein pathology and synaptic function in vulnerable dopaminergic neurons. [doi:10.25345/C5PG1J14X] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: NALL ; synuclein ; synaptic function ; PD ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		jeffrey Savas, Northwestern University Feinberg, United States
Submitting User: jeffsavas
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