FDA-Approved Compound Shows Promise in Protecting Against Parkinson’s Disease

A compound already approved for use in treating a rare genetic disease is showing promising neuroprotective effects in experimental models of Parkinson’s disease, according to a recent study published in The Journal of Clinical Investigation. Researchers at Northwestern Medicine have found that N-acetyl-L-leucine, or NALL, appears to impact several key pathways involved in the development and progression of Parkinson’s, offering a potential new avenue for treatment.

Parkinson’s disease is a progressive neurological disorder that affects movement. It’s caused by the loss of dopamine-producing neurons in the brain. Even as current treatments can help manage symptoms, there is no cure, and no way to unhurried or stop the disease’s progression. This is why research into potential disease-modifying therapies is so critical.

How NALL Works: Targeting Multiple Pathways

The study, led by PingPing Song, PhD, research associate professor in the Ken and Ruth Davee Department of Neurology’s Division of Movement Disorders at Northwestern University’s Feinberg School of Medicine, and Dimitri Krainc, MD, PhD, chair of Neurology, demonstrates that NALL isn’t acting on just one aspect of the disease. Instead, it simultaneously influences multiple molecular pathways in dopaminergic neurons – the very cells affected in Parkinson’s. These pathways include alpha-synuclein pathology, synaptic function, lysosomal pathways, and mitochondrial proteins. The full study details these findings.

Alpha-synuclein is a protein that forms clumps in the brains of people with Parkinson’s. These clumps, known as Lewy bodies, are thought to contribute to the death of dopamine-producing neurons. Synapses are the connections between neurons, and their dysfunction is an early feature of Parkinson’s. Lysosomes are responsible for clearing out cellular waste, and their impairment can lead to the buildup of toxic proteins. Mitochondria are the powerhouses of cells, and their dysfunction can lead to energy deficits.

“This function demonstrates that NALL can influence several Parkinson’s disease-relevant pathways, suggesting broader relevance for neurodegeneration,” Dr. Song explained. The researchers generated dopaminergic neurons from induced pluripotent stem cells derived from patients with both familial and sporadic forms of Parkinson’s disease. Treating these neurons with NALL revealed positive changes in pathological and functional markers.

Enhancing Clearance and Restoring Function

The research team identified two key mechanisms through which NALL exerts its neuroprotective effects. First, NALL appears to enhance the clearance of the problematic alpha-synuclein protein by boosting the activity of an enzyme called HTRA1. HTRA1 can break down or disaggregate these protein clumps. Second, NALL restores presynaptic dopamine function by increasing levels of a protein called parkin. Parkin plays a role in dopamine transporter maturation, synaptic vesicle recycling, and overall dopamine signaling.

This dual action is significant. Reducing toxic protein buildup and strengthening synaptic connections could address both the underlying causes and the symptoms of Parkinson’s. The researchers validated these findings using mouse models of Parkinson’s disease, observing improvements in alpha-synuclein pathology and motor learning behavior in mice treated with NALL.

A Familiar Compound with a New Potential

NALL isn’t a completely new entity. It’s an amino acid derivative of leucine and has been used for decades outside of the United States to treat acute vertigo and vestibular disorders – conditions causing dizziness and balance problems. Technology Networks provides further background on the compound’s history. Importantly, in 2024, the FDA approved NALL for the treatment of Niemann-Pick disease type C1, a rare genetic disorder, which demonstrates its established safety profile in humans. This existing safety data could potentially accelerate the process of bringing NALL to clinical trials for Parkinson’s disease.

Beyond Parkinson’s: Implications for Other Neurodegenerative Diseases

The potential benefits of NALL may extend beyond Parkinson’s. Dr. Song suggests that the compound’s ability to target alpha-synuclein pathology and improve synaptic function could have relevance for other neurodegenerative disorders, such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia. HTRA1, the enzyme boosted by NALL, is capable of targeting multiple aggregation-prone proteins, making it a potentially valuable therapeutic target across a range of conditions.

Understanding the Study’s Limitations

While these findings are encouraging, it’s crucial to remember that this research is still in its early stages. The study was conducted in experimental models – cell cultures and mice – and the results may not directly translate to humans. Further research is needed to determine the optimal dosage of NALL, its long-term effects, and its efficacy in different stages of Parkinson’s disease. The study as well focused on specific genetic forms of Parkinson’s; more research is needed to understand how NALL might affect individuals with sporadic Parkinson’s, which accounts for the vast majority of cases.

What’s Next for NALL Research?

The Northwestern team is already planning further investigations. They aim to understand precisely how NALL induces HTRA1 expression, whether it impacts mTOR signaling or leucine-sensing pathways, and whether the increase in PRKN (the gene encoding parkin) occurs directly or indirectly. Future studies will also explore NALL’s potential in other neurodegenerative diseases. Controlled clinical trials in Parkinson’s disease patients will be necessary to evaluate the compound’s disease-modifying potential and determine its efficacy, particularly in the early or prodromal stages of the disease. Details of the molecular mechanisms are available through the National Library of Medicine.

The discovery of NALL’s neuroprotective effects represents a significant step forward in the search for new Parkinson’s disease treatments. While much work remains to be done, the compound’s existing safety profile and its ability to target multiple disease pathways offer a glimmer of hope for those affected by this debilitating condition.