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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 α-synuclein pathology and synaptic function in vulnerable dopaminergic neurons.
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