Small Molecule, Big Hope—Can Acetyl‐<scp>DL</scp>‐Leucine Reverse Parkinson's Disease?

Oertel WH, Janzen A, Henrich MT, Geibl FF, Sittig E, Meles SK, Carli G, Leenders K, Booij J, Surmeier DJ, Timmermann L, Strupp M. Acetyl-DL-leucine in two individuals with REM sleep behavior disorder improves symptoms, reverses loss of striatal dopamine-transporter binding and stabilizes pathological metabolic brain pattern-case reports. Nat Commun 2024;15(1):7619. doi: 10.1038/s41467-024-51502-7. Recently, N-acetyl-L-leucine has been reported to have disease-modifying effects in Niemann-Pick disease type C, a lysosomal storage disorder, in a randomized controlled trial.1 Lysosomal dysfunction is also thought to be one of the underlying pathogenic mechanisms of Parkinson's disease (PD), which often manifests with rapid eye movement sleep behavior disorder (RBD) as prodrome. Oertel and colleagues2 treated two individuals with isolated RBD (iRBD), hyposmia, and pathological dopamine-transporter single-photon emission computerized tomography (DAT-SPECT) with acetyl-DL-leucine (ADLL) (5 g/d; contains a racemate of acetyl-leucine, the inactive D-form, and the bioactive enantiomer, the L-form) for 18 and 22 months, respectively, and investigated its effect on disease progression using the following outcome parameters: RBD-severity sum-score (RBD-SS-3; a RBD diary filled by patient and bedpartner), DAT-SPECT imaging (performed in two centers) and metabolic “Parkinson-Disease-Pattern (PDRP)”-z-score in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET).2 They report no side effects and that ADLL therapy improved the severity of RBD in terms of reduction of aggressive dream content and dream enactment, reversed the loss of striatal dopamine transporter binding, and stabilized the metabolic FDG-PET pattern. The authors acknowledge several limitations: the report encompassing only two cases without a placebo control; the lack of a pre-defined protocol for the timing of imaging assessment; the method of PDRP by FDG-PET being not yet fully established; the subjective nature of the RBD diary as outcome measure (in contrast to objective measures like polysomnography). Moreover, reduced dream-enacting behavior alone cannot be equated with improvement in RBD, and it is not yet clear that RBD severity (or the content of dreams in RBD) correlates well with overall disease progression and severity. Data from the Parkinson's Progression Markers Initiative (PPMI) cohort suggest, for example, four different variations of how RBD develops during the disease course including stabilization, or even reversal, of RBD.3 Another caveat pertains to the serial DAT-SPECT imaging as a biomarker, because it can be influenced by a number of technical and pharmacokinetic factors, and has, therefore, been critically discussed as a trial endpoint.4 Interestingly, the bacterial leucine transporter is a homolog of DAT, and binding sites for the substrate ligands (dopamine and amphetamine) overlap with the analogous region for the substrate leucine.5 Given that DAT binding may reflect axonal dysfunction or DAT expression rather than the number of viable neurons, this raises the question if ADLL is truly reversing disease, or if its effects might be more symptomatic. N-acetyl-DL-leucine has been commercially available for the treatment of vertigo since 1957. Its exact mechanism of action is not known, but at a molecular level, several mechanisms of action have been suggested including direct action on glycine and AMPA receptors, and effects on glutamate neurotransmission.6 Of note, the therapeutic effects are ascribed to the L-enantiomer, and it appears that there are significant pharmacokinetic differences between the two N-acetyl-DL-leucine enantiomers. In summary, the use of N-acetyl-leucine for the treatment of prodromal phases of α-synuclein related neurodegenerative disease represents another interesting example of drug-repurposing and a tantalizing avenue to explore, with further studies needed to address and clarify the above-mentioned limitations and caveats—watch this space! (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. B.B.: 3A. K.B.: 3B. Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the previous 12 months: B.B. has received funding from the Hurka Foundation, the Olga Mayenfisch Foundation and the Betty and David Koetser Foundation, and has received royalties from Oxford University Press. K.P.B. receives royalties from publication of the Oxford Specialist Handbook Parkinson's Disease and Other Movement Disorders (Oxford University Press, 2008), Marsden's Book of Movement Disorders (Oxford University Press, 2012), and Case Studies in Movement Disorders: Common and Uncommon Presentations (Cambridge University Press, 2017); and has received honoraria/personal compensation for participating as consultant/scientific board member from Ipsen, Allergan, and Merz; and honoraria for speaking at meetings from Allergan, Ipsen, Merz, Sun Pharma, Teva, and UCB Pharmaceuticals and from the American Academy of Neurology and the International Parkinson's Disease and Movement Disorders Society.