FDA-Approved Compound Shows Neuroprotective Effects in Parkinson's Disease Models

Northwestern Medicine scientists have discovered an FDA-approved compound promotes neuroprotective effects in experimental models of Parkinson's disease, according to a recent study published in The Journal of Clinical Investigation. The compound, N-acetyl-L-leucine (NALL), simultaneously targets multiple molecular pathways in dopaminergic neurons impacted by Parkinson's disease, underscoring NALL's potential therapeutic benefit in treating the disease in humans.

NALL is an amino acid derivative of the branched-chain amino acid leucine. For decades, NALL has been used outside the U.S. to treat acute vertigo and vestibular disorders, which can cause dizziness and issues with balance. In 2024, NALL received FDA approval for the treatment of Niemann-Pick disease type C1, a rare genetic disease that causes progressive neurological symptoms and organ dysfunction, further supporting NALL's safety in humans.

To investigate the underlying mechanisms of NALL in Parkinson's disease, the scientists generated dopaminergic neurons from induced pluripotent stem cells derived from patients with different forms of familial and sporadic Parkinson's disease and then treated these neurons with NALL to examine pathological and functional changes. The investigators performed a series of biochemical and molecular analyses to identify molecular pathways altered by NALL. To validate their findings in vivo, the scientists used mouse models of LRRK2-mutant Parkinson's disease: mice were given an oral NALL treatment and evaluated the compound's effects on alpha-synuclein pathology, expression and dopamine-dependent motor learning behavior.

Using this multi-pronged approach, the scientists established that NALL promotes neuroprotective effects through two key mechanisms. First, NALL enhances the clearance of pathogenic α-synuclein by inducing the HTRA1 enzyme, which can degrade or disaggregate alpha-synuclein aggregates. Second, they found that NALL restores presynaptic dopamine function by increasing parkin levels, which promotes dopamine transporter maturation, enhances synaptic vesicle recycling, and improves dopamine signaling.

The work demonstrates that NALL can influence several Parkinson's disease-relevant pathways, including alpha-synuclein pathology, synaptic function, lysosomal pathways and mitochondrial proteins, suggesting broader relevance for neurodegeneration. This identifies a potential therapeutic pathway for alpha-synucleinopathies, including Parkinson's disease, and possibly other neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, since HTRA1 is capable of targeting multiple aggregation-prone proteins.

The results suggest that NALL not only reduces toxic protein aggregation but also strengthens synaptic resilience, further supporting NALL as a promising therapeutic candidate that can target several key mechanisms involved in Parkinson's disease simultaneously. In addition, by improving synaptic function, NALL may help address early synaptic dysfunction that occurs before significant neuronal loss in Parkinson's disease. Importantly, because NALL already has established clinical safety data, these results could help accelerate its translation into clinical trials aimed at developing disease-modifying therapies for Parkinson's disease.

The next steps for this work will include studying how NALL induces HTRA1 expression, whether it regulates mTOR signaling or leucine-sensing pathways, and whether PRKN increase occurs directly or indirectly. Future studies should also explore the therapeutic potential of NALL in other neurodegenerative disorders such as ALS, frontotemporal dementia and Alzheimer's disease. Controlled clinical trials in Parkinson's disease will be needed to evaluate the optimal dosing of NALL, determine whether it has disease-modifying potential and assess its efficacy in early or prodromal stages of the disease.