aMolecular Neurobiology Laboratory, Program in Neuroscience, Harvard Medical School, Boston, MA 02115;
bDepartment of Psychiatry, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478
Parkinson’s disease (PD) is, after Alzheimer’s disease, the second most-common neurodegenerative disorder affecting 1-2% of the global population over the age of 65 (1, 2). Aging being a primary risk factor for PD (3), its economic burden on our society in terms of medical care will escalate with our aging population. The major pathophysiological features of PD include selective and progressive degeneration of A9 midbrain dopaminergic (mDA) neurons in the substantia nigra and widespread accumulation of intraneuronal proteinaceous inclusions, called Lewy bodies, whose major component is misfolded α-synuclein. A9 DA neurons project to the dorsal striatum and form the nigrostriatal pathway, which controls voluntary movements. Degeneration of this pathway in PD patients results in decreased dopamine levels in the striatum, leading to clinical manifestations, such as resting tremor, rigidity, bradykinesia, and gait dysfunctions (1, 2). Since its introduction in the 1960s, dopamine replacement therapy through levodopa (l-dopa) and DA agonist administration remain the standard treatment for PD (4). Although this pharmacological treatment dramatically improves the quality of life of numerous PD patients, its efficacy wanes over time and the need for increased dosage eventually induces severe side effects, such as dyskinesia. Although there are alternative surgical treatments, such as deep brain stimulation (5), both forms of treatment are symptomatic and cannot stop or modify the disease progression. Therefore, there is a significant unmet need for the development of novel neuroprotective and disease-modifying therapeutics for PD. In PNAS, Spathis et al. (6) introduce a novel compound, BRF110, which is a unique Nurr1: retinoid X receptor-α (RXRα)-selective “agonist” that can prevent DA neurons’ demise and striatal DA denervation in vivo in several preclinical models of PD. Remarkably, this study shows that BRF110 is not only neuroprotective in sparing mDA neurons, but also upon a single administration led to significant …
1To whom correspondence may be addressed.