Inflammation and Parkinson's disease pathogenesis: Mechanisms and therapeutic insight.

Abstract

After Alzheimer's disease, Parkinson's disease is the most frequent neurodegenerative disorder. Although numerous treatments have been developed to control the disease symptomatology, with some successes, an efficacious therapy affecting the causes of PD is still a goal to pursue. The genetic evidence and the identification of α-synuclein as the main component of intracellular Lewy bodies, the neuropathological hallmark of PD and related disorders, have changed the approach to these disorders. More recently, the detrimental role of α-synuclein has been further extended to explain the wide spread of cerebral pathology through its oligomers. To emphasize the central pathogenic role of these soluble aggregates, we have defined synucleinopathies and other neurodegenerative disorders associated with protein misfolding as oligomeropathies. Another common element in the pathogenesis of oligomeropathies is the role played by inflammation, both at the peripheral and cerebral levels. In the brain parenchyma, inflammatory reaction has been considered an obvious consequence of neuronal degeneration, but recent observations indicate a direct contribution of glial alteration in the early phase of the disease. Furthermore, systemic inflammation also influences the development of neuronal dysfunction caused by specific elements, β amyloid, α-synuclein, tau or prion. However, each disorder has its own specific pathological process and within the same pathological condition, it is possible to find inter-individual differences. This heterogeneity might explain the difficulties developing efficacious therapeutic approaches, even though the possibility of intervention is supported by robust biological evidence. We have recently demonstrated that peripheral inflammation can amplify the neuronal dysfunction induced by α-synuclein oligomers and the neuropathological consequences observed in a Parkinson's disease model. In both cases, activation of microglia was incremented by the "double hit" process, compared to the single treatment. In contrast, astrocyte activation was attenuated and these cells appeared damaged when chronic inflammation was combined with α-synuclein exposure. This evidence might indicate a more specific anti-inflammatory strategy rather than the generic anti-inflammatory treatment.