Future directions for immune modulation in neurodegenerative disorders: focus on Parkinson's disease.

ABSTRACT

One common feature of neurodegenerative diseases is neuroinflammation. In the case of Parkinson's disease (PD), neuroinflammation appears early and persists throughout the disease course. The principal cellular mediator of brain inflammation is the resident microglia which share many features with related hematopoietically derived macrophages. Microglia can become activated by misfolded proteins including the PD relevant example, alpha-synuclein, a presynaptic protein. When activated, microglia release pro-inflammatory diffusible mediators that promote dysfunction and contribute to the death of the PD vulnerable dopaminergic neurons in the midbrain. Recently, the orphan nuclear receptor Nurr1, well known as a critical determinant in dopaminergic neuron maturation, has been ascribed two new properties. First, it promotes the production and release of the neuropeptide vasoactive intestinal peptide that functions both to stimulate dopaminergic neuron survival and inhibit neuroinflammation. Second, Nurr1 suppresses the expression and release of pro-inflammatory cytokines in glial cells. Herein, we discuss these new findings in context of strategies to attenuate neuroinflammation in PD.