Leaky gut, dysbiosis, and enteric glia activation: the trilogy behind the intestinal origin of Parkinson's disease

how we can improve the therapeutic approach: PD is a neurodegenerative disease characterized by motor dysfunctions (tremor, rigidity, bradykinesia and impaired posture/balance) elicited by selective depletion of dopaminergic (DA) neurons in substantia nigra pars compacta. DA neuron loss is associated with neuronal inclusions of the phosphorylated α-synuclein protein called Lewy body (Shults, 2006). Although the underlying neurodegenerative process is not affected, the management of PD patients has been revolutionized with the introduction of levodopa and DA drugs in the routine therapy, which ensures initial symptomatic relief of motor functions through the DA supply in the nigrostriatal circuit. These drugs are currently the best option for treating PD, although their chronic use is associated with progressive dopamine resistance and loss of effectiveness in the recovery of motor dysfunctions. Alternative therapeutic strategies, including agonists of DA receptors, monoamine oxide B inhibitors, and even deep brain stimulation techniques have been developed to overcome these clinical limitations. Unfortunately, these therapeutic approaches cannot restore PD-compromised functions, as irreversible DA neurodegeneration has occurred in substantia nigra pars compacta when first motor symptoms appear. The nigrostriatal system is traditionally considered as the first region affected by neuronal impairment in Parkinsonisms; however, α-synuclein aggregation appears in a pre-motor stage of the disease in the enteric nervous system (ENS), strongly highlighting an extra-central nervous system (CNS) origin for this neurodegenerative disorder and completely overturning the concept of PD as a central disease. The “ability” of the gut to show the pre-symptomatic evolution of PD is a very fascinating hypothesis to anticipate PD diagnosis and develop more efficient anti-Parkinsonian drugs. In this perspective article, we summarize recent evidence showing enteric glia involvement triggering intestinal neuroinflammation in the asymptomatic stage of PD and improvements in the therapeutic approach that we could achieve by targeting these glial cells.