Brain-liver axis: metabolic link and therapeutic target in Parkinson’s disease – MetaPark

Aging is recognized as the greatest risk factor for developing idiopathic Parkinson’s disease (PD). However, this axiom is solely supported by epidemiological observations. Several processes such as the gradual loss of nigral dopamine neurons and the accumulation the protein alpha-synuclein occur during physiological aging and are exacerbated in the context of PD resulting in a severe neurodegeneration and the appearance of Lewy bodies. Both physiological and pathological aging manifest as a multi-system deterioration. Thereby, over the course of the disease, PD patients will often develop other age-related comorbidities such as diabetes, cancer, constipation, or dementia. These observations suggest the putative involvement of metabolic pathways leading towards pathological cerebral aging.
Despite several mammalian genes and signaling pathways exert an effect on longevity, their involvement in the context of PD remains completely uncharted. Also, aging represents a major hurdle for modeling PD pathology in cell and animal models with the consequence of impeding the discovery of a cure. Therefore the elucidation of signals governing neuronal senescence would bring important insight into the development of age-related brain disorders and would open tremendous opportunities for therapeutic interventions.
In a recent effort to identify modifiers of alpha-synuclein toxicity, our unbiased high-content screening approach revealed the insulin-like growth factor 1 (IGF-1) pathway as an interesting target. The IGF-1 signaling is the best-characterized regulator of longevity as its inhibition increases lifespan across species. In humans, reduced levels of serum IGF-1 are associated with healthy aging. In contrast, studies reported an increase of this parameter in de novo, unmedicated PD patients, however its significance remains elusive.
Using pharmacological and genetic approaches in complementary models of PD, we recently demonstrated that brain-targeted inhibition of the IGF-1 pathway affords robust protective and regenerative effects on nigral dopamine neurons. Based on our results, we hypothesize that IGF-1 may exert a pro-aging effect that primes the brain to develop age-related diseases such as PD. In addition, we postulate that lowering circulating IGF-1 levels may provide an interesting therapeutic option. Since the liver produces 80% of circulating IGF-1, we propose as a next step to modulate its hepatic production and to explore the effects in physiological and pathological conditions. To this end, we have designed the MetaPark project along the following 4 tasks.
In the first task, we will confirm the elevation of IGF-1 levels in PD patients and we will try to elucidate its relevance by examining samples from patients with extreme variations in the expression of this hormone. In the second task, we will clarify the chicken or the egg causality dilemma by assessing the consequence of striatal dopaminergic depletion on the level of circulating IGF-1. Thirdly, we will determine whether over-production of IGF-1 by the liver can trigger or exacerbate PD pathology in mice. In the final task, we will determine whether viral vector-mediated repression of liver-derived IGF-1 can provide a therapeutic effect in a relevant mouse model of PD.
The MetaPark project holds the potential to validate IGF-1 as a metabolic substrate linking PD to its greatest risk factor and to offer an innovative and clinically relevant therapeutic strategy for PD.