Low Doses of Leukemia Drug Clear Toxic Proteins and Improve Symptoms in Mouse Models of Parkinson’s Disease

Researchers at Georgetown University Medical Center report that very small doses of a leukemia medication can prevent the accumulation of toxic proteins associated with Parkinson’s disease in mice. Published online May 10 in Human Molecular Genetics, the study outlines a promising strategy to stimulate neuronal protein clearance, offering a potential treatment approach for several neurodegenerative disorders marked by abnormal protein buildup.

The team found that nilotinib, a drug approved to treat chronic myelogenous leukemia (CML), activates autophagy — the cell’s internal “garbage disposal” system — at low doses. By enhancing this natural clearance process in neurons, nilotinib reduced intracellular deposits of pathogenic proteins such as alpha-synuclein and tau, limiting their formation into Lewy bodies, tangles, or extracellular plaques that contribute to brain damage.

When used at the high doses required for CML, nilotinib drives aggressive autophagy that can lead to tumor cell death. The investigators reasoned that a much lower dose could produce a gentler activation of autophagy in neurons — sufficient to remove defective or aggregated proteins without harming cells. In the mouse experiments, animals that overexpress alpha-synuclein, a protein central to Parkinson’s disease and Lewy body dementia, received one milligram of nilotinib every two days. For perspective, standard clinical doses for CML reach up to 1,000 milligrams once a day.

The study demonstrates that this low-dose treatment substantially reduced levels of alpha-synuclein and tau in the brains of treated mice. Importantly, animals receiving nilotinib also showed notable improvements in motor function and behavior compared with untreated mice, indicating that protein clearance translated into meaningful functional benefits in these disease models.

Investigators selected nilotinib (and identified bosutinib as an additional candidate) because these compounds can cross the blood-brain barrier — a crucial requirement for any drug intended to act on neurons. The research team, led by neuroscientist Charbel E.-H. Moussa, PhD, screened cancer drugs known to promote autophagy and prioritized those with the ability to reach brain tissue. The present publication focuses on the results with nilotinib, while noting that related drugs may offer similar advantages.

Clearing intracellular protein aggregates early in the disease process may be most effective. The authors suggest that initiating therapy before extensive extracellular plaque formation or widespread inclusion body accumulation should provide the best chance to preserve neuronal function. Even when started later, however, enhancing autophagy could slow further progression by reducing additional protein deposition.

Notes about this research and further plans

The research received support from a National Institutes of Health grant (NIA 30378) and internal funding from Georgetown University. Following these preclinical results, the senior investigator is planning a phase II clinical trial to evaluate safety and efficacy in people diagnosed with disorders characterized by alpha-synuclein accumulation, including Lewy body dementia, Parkinson’s disease, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA).

Charbel E.-H. Moussa is listed on a provisional patent application covering the use of nilotinib and bosutinib as therapeutic agents for neurodegenerative diseases. The authors emphasize that while these results are promising in mouse models, human clinical trials are necessary to determine safety, optimal dosing, and clinical benefit in patients.

The study highlights a broader therapeutic concept: repurposing existing drugs that modulate cellular clearance pathways to target neurodegenerative disorders. By selectively boosting autophagy in neurons, researchers aim to reduce the toxic burden of misfolded or aggregated proteins — a common pathological feature across Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Huntington’s disease, and Lewy body dementias.

Overall, the findings represent a significant preclinical step toward translating an autophagy-based approach into human studies. If subsequent clinical trials confirm safety and efficacy, low-dose nilotinib or similar agents could become part of a therapeutic toolkit designed to slow or prevent the progression of multiple proteinopathy-driven brain diseases.

Contact: Karen Mallet – Georgetown University Medical Center
Source: Georgetown University Medical Center press release
Image Source: The brain image is credited to NIA/NIH and is in the public domain.
Original Research: Abstract for “Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson’s disease models” by Michaeline L. Hebron, Irina Lonskaya and Charbel E.-H. Moussa in Human Molecular Genetics. Published online May 10, 2013. doi: 10.1093/hmg/ddt192