Ketones on the Brain: Can Diet Help Turn the Tables on Parkinson's?—Commentary on Mahajan et al. (2024)

Abstract

While disease-modifying therapeutics for Parkinson's disease (PD) remain elusive, lifestyle changes are promising but often overlooked options for diminishing symptoms and slowing disease progression. Ketogenic diet (KD), first touted a century ago as a treatment for epilepsy, has shown encouraging signs as an alternative therapy for idiopathic PD (Vanitallie et al. 2005). Deficits in neuronal metabolism are central contributors to many neurodegenerative diseases (Yang, Park, and Lu 2023), and patients with PD exhibit deficiencies in mitochondrial complex I function (González-Rodríguez et al. 2021). Neurons are capable of oxidizing ketone bodies as an alternative energy source that can bypass complex I, providing a potential mechanism to boost energy production in the face of poorly functioning mitochondria (Tieu et al. 2003). Pre-clinical studies using the complex I inhibitor 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) demonstrate that KD can prevent motor dysfunction and dopaminergic degeneration associated with this PD model (Jiang et al. 2023; Yang and Cheng 2010; Zhang et al. 2023). Exposure to KD prior to MPTP or lipopolysaccharide treatment promotes neuroprotective and anti-inflammatory effects in the brain (Fu et al. 2015; Yang and Cheng 2010), attenuates glial activation and promotes beneficial changes in gut microbiota (Jiang et al. 2023; Zhang et al. 2023). In a recent issue of EJN, Mahajan and colleagues (Mahajan et al. 2024) expanded on this work by exploring two questions: (1) Could a ketone-rich diet be a useful intervention in a progressive genetic model of mitochondrial dysfunction in PD? and (2) Can ketone supplementation be neuroprotective when given post-symptomatically?

To accomplish this, the authors used the phenotypically-faithful MitoPark mouse model of PD, which is a dopamine neuron-specific knockout of mitochondrial transcription factor A (Tfam) (Ekstrand et al. 2007). Tfam drives expression of mitochondria-encoded genes including those that are essential for respiratory chain function. This model mimics several key aspects of clinical PD progression, including adult-onset and age-dependent degeneration of dopamine neurons in the substantia nigra pars compacta, producing catastrophic motor failure (Beckstead and Howell 2021). When the authors administered a ketone ester-enriched diet (KEED) to MitoPark mice beginning prior to the emergence of obvious motor deficits, they observed a substantial retention of locomotion and rotarod performance. This was accompanied by a modest improvement in striatal dopamine release, but interestingly, no clear preservation of the neurons themselves (i.e., survival). Further, some benefit was also observed when KEED was initiated at a later time point, following appearance of motor symptoms, suggesting that dietary interventions may be useful in PD patients even at more advanced stages of the disease. The authors conclude that in MitoPark mice, KEED works by enhancing or preserving mitochondrial bioenergetics, dopamine synthesis and vesicular packaging. This is the first time that a ketone diet has shown benefit in a progressive model of PD or when treatment was initiated following the appearance of symptoms.

While the study did not directly test cellular mechanisms, the data point to several compelling possibilities. Neurons rely heavily on oxidative phosphorylation (OXPHOS) to generate energy (Demetrius, Magistretti, and Pellerin 2015), and dopamine neurons are particularly susceptible to degeneration given their extensive axonal arbours, high calcium handling and spontaneous firing that constantly requires replenishment of intracellular and vesicular ion gradients. Distal axons may be particularly susceptible to neurodegeneration due to compromised mitochondrial protein quality and a decreased ability to maintain energetic homeostasis (Yang, Park, and Lu 2023). The ketone bodies provided by the KEED were apparently able to act as an effective energy substrate in the face of mitochondrial dysfunction and oxidative stress (Zhang et al. 2023). Furthermore, the ketone body β-Hydroxybutyrate (βHB) has been previously shown to protect neurons from MPTP by enhancing ATP production in a manner dependent on mitochondrial complex II (Tieu et al. 2003). Another potential mechanism suggested by the data is an increase of dopamine synthesis due to enhanced availability of tetrahydrobiopterin (BH4), which serves as a co-factor for tyrosine hydroxylase in the synthesis of catecholamines (Nagatsu 2024). When ketone bodies enter the TCA cycle, they increase the availability of NADPH which in turn contributes to the synthesis of BH4 (Soula et al. 2020). KD could therefore be a strategy to bypass declining complex I function while potentially increasing dopamine synthesis in the surviving dopamine neurons. Finally, ketone administration likely alters the gut microbiota and its metabolites (Jiang et al. 2023; Zhang et al. 2023), ameliorating parkinsonian symptoms through regulation of the gut-brain axis.

Despite showing promise, substantial challenges could yet derail the regular use of KDs to improve quality of life in PD patients. Strict diet regimes can be difficult to implement and can have low compliance, and prolonged use of KDs can induce side effects such as increased LDL levels (Veech et al. 2001). Additionally, patients with PD often face additional challenges, as movement difficulties hinder food preparation, loss of smell can reduce palatability, and constipation common with PD could be worsened by a low fibre KD. Although large, long-term studies of KD in patients with PD have not been conducted, one encouraging feasibility study showed that with the help of a dietician, 5 out of 7 patients with PD were able to prepare and adhere to a KD (Vanitallie et al. 2005). Age is a leading risk factor in idiopathic PD, and aging itself may produce a compensatory increase in OXPHOS proteins (Stauch, Purnell, and Fox 2014), potentially priming the cells for an increase in energetic supply provided by dietary ketones. In contrast, recent work suggests that parkinsonian neurons may actually undergo a Warburg-type metabolic shift that favours glycolysis over OXPHOS (González-Rodríguez et al. 2021). If this occurs during disease progression, it would limit the time window through which ketone supplementation may be an effective treatment. Despite these barriers, results from Mahajan et al. and multiple other studies encouragingly support that KD may one day be a critical part of a holistic intervention for at least a subset of patients with PD and is worthy of further study. Strategies to increase oxidative capacity may also be of value for enhancing or prolonging the beneficial effects of ketones in the treatment of PD.

Ana Luiza Drumond-Bock: conceptualization, writing – original draft, writing – review and editing. Michael J. Beckstead: conceptualization, funding acquisition, writing – review and editing.

The authors declare no conflicts of interest.