An 8-year-old patient with gangliosidosis (a rare, inherited lysosomal storage disorder that destroys nerve cells) demonstrates improved mobility, walking unassisted on a soccer field after treatment with N-acetyl-L-leucine. Both gangliosidosis and Niemann-Pick Type C (for which N-acetyl-L-leucine is FDA-approved) are primary lysosomal storage disorders, a disease category with emerging links to other neurodegenerative conditions. (Still from video footage; parental consent obtained for use).
N-acetyl-L-leucine (NALL), an FDA-approved drug for Niemann-Pick disease Type C from IntraBio may hold promise for Parkinson’s disease (PD). A pre-print manuscript posted on Research Square (currently under review at a Nature Portfolio journal) details the relevant preclinical research of the mode of action. It indicates that NALL directly reduces pathological alpha-synuclein, upregulates protective proteins like parkin, and improves synaptic function in cellular and animal models of Parkinson’s disease.
hTe hope is that NALL, by targeting some of the core cellular problems believed to drive Parkinson’s, such as the buildup of toxic proteins and damage to nerve cell connections, could offer a new, disease-modifying approach. The strategy involves repurposing a drug already known to be safe in humans for one neurological condition (Niemann-Pick Type C) to potentially treat another, more common one.
In laboratory experiments using nerve cells derived from Parkinson’s patients, NALL treatment showed encouraging effects by reducing a key toxic protein implicated in the disease and boosting a protective one. Specifically, in GBA1 L444P patient-derived dopaminergic neurons, four weeks of treatment with 10 mM NALL reduced Triton-soluble phosphorylated α-synuclein by roughly 45% (n=4, p<0.01, Fig. 1 in the pre-print) and Triton-insoluble phosphorylated α-synuclein by about 50% (n=4, p<0.01, Fig. 1). In the same L444P neuronal model, parkin levels were increased by about 70% with 10 mM NALL (n=3, p<0.05, Fig. 3). Effects on phosphorylated α-synuclein varied across different genetic backgrounds, with reductions at 5mM or 10mM NALL ranging from roughly 30% to 60% observed in GBA1 N370S and LRRK2 R1441C neurons (Fig. 1, Fig. 4).
A September 2024 case report in Nature Communications (Oertel, Strupp et al.) described symptomatic improvement and positive changes in key neuroimaging biomarkers (DAT-SPECT and FDG-PET) in two individuals with REM Sleep Behavior Disorder (a prodromal PD state) treated with acetyl-DL-leucine.
More than 10 million people live with Parkinson’s worldwide, and prevalence is increasing. Current drugs target motor symptoms, not underlying pathology. A readily available molecule with a known safety profile could shorten the road to a true disease-modifier.
Filed Under: Neurological Disease
