N-acetyl-l-leucine lowers α-synuclein levels and improves synaptic function in Parkinson’s disease models
Pingping Song, Chuyu Chen, Rossella Franchini, Bryan Duong, Yi-Zhi Wang, Robert Coukos, Zhong Xie, Jeffrey N. Savas, Yueqin Zhou, Mariarita Bertoldi, D. James Surmeier, Loukia Parisiadou, Dimitri Krainc
Pingping Song, Chuyu Chen, Rossella Franchini, Bryan Duong, Yi-Zhi Wang, Robert Coukos, Zhong Xie, Jeffrey N. Savas, Yueqin Zhou, Mariarita Bertoldi, D. James Surmeier, Loukia Parisiadou, Dimitri Krainc
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Research Article Cell biology Neuroscience

N-acetyl-l-leucine lowers α-synuclein levels and improves synaptic function in Parkinson’s disease models

Abstract

N-acetyl-l-leucine (NALL), a derivative of the branched-chain amino acid leucine, has shown therapeutic potential for neurodegenerative diseases, including in prodromal stages of Parkinson’s disease (PD). However, the mechanism of its protective effects has been largely unknown. Using human induced pluripotent stem cell–derived dopaminergic neurons from patients carrying GBA1, LRRK2, or VPS35 mutations, as well as from sporadic PD cases, we found that NALL treatment markedly reduced Ser129 phosphorylated α-synuclein (pS129-syn). Discovery-based proteomic analysis revealed that NALL treatment upregulated lysosomal, mitochondrial, and synaptic proteins without inducing cytotoxicity. The reduction of pS129-syn was dependent on serine protease HTRA1, which was robustly induced by NALL. Moreover, NALL increased the expression of wild-type parkin in mutant dopaminergic neurons, leading to increased glycosylated dopamine transporter, elevated synaptic membrane-associated synaptojanin-1, and accelerated synaptic vesicle endocytosis, suggesting improved synaptic function. Furthermore, in LRRK2R1441C knockin mice, NALL administration decreased pS129-syn, elevated parkin levels, and ameliorated dopamine-dependent motor learning deficits. These findings highlight the therapeutic potential of NALL for PD by its protective effects on α-synuclein pathology and synaptic function in vulnerable dopaminergic neurons.

Authors

Pingping Song, Chuyu Chen, Rossella Franchini, Bryan Duong, Yi-Zhi Wang, Robert Coukos, Zhong Xie, Jeffrey N. Savas, Yueqin Zhou, Mariarita Bertoldi, D. James Surmeier, Loukia Parisiadou, Dimitri Krainc

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Figure 6

NALL improves dopamine-dependent motor learning impairments in LRRK2R1441C mice.

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NALL improves dopamine-dependent motor learning impairments in LRRK2R144...
(A) Schematic of the rotarod training paradigm. LRRK2R1441C mice were evaluated over a total of 18 daily sessions, with each session consisting of 5 trials. The mice were administered either NALL or a vehicle control intraperitoneally 30 minutes before receiving either saline or a cocktail of dopamine D1 receptor antagonists (SCH23390) and D2 receptor antagonists (eticlopride), both at a dosage of 1 mg/kg. Thirty minutes after injection, mice were trained on an accelerating rotarod for 5 consecutive days. After a 72-hour break, mice were returned to the rotarod for an additional 13 days, with either NALL or vehicle administered 60 minutes before each session. (B) LRRK2R1441C mice that received NALL exhibited improved rotarod performance — indicated by the latency to fall from the rotarod — compared with vehicle-treated controls (treatment P = 0.0013, session P < 0.0001, treatment × session factor P < 0.0001, subject P < 0.0001). (C) Summary of average latency to fall in session 1, session 6, and session 18 from B. Statistical significance was determined by 2-way repeated measures ANOVA followed by Tukey’s multiple comparisons test (*P < 0.05, ***P < 0.005). n = 10 mice per treatment group.