Abstract:

Parkinson´s disease (PD) is characterized by the progressive loss of midbrain dopaminergic (mDA) neurons and a subsequent decrease in striatal dopamine levels which cause the typical clinical motor symptoms such as muscle rigidity, bradykinesia and tremor. Although a subset of PD cases has been described to arise from inherited mutations of genes such as α-Synuclein or Lrkk2, the majority of PD cases develop spontaneously. Despite intensive research, the molecular mechanisms underlying degeneration of mDA neurons are only poorly understood. Interestingly, a common hallmark of virtually all PD cases is a neuroinflammatory response that is predominantly mediated by microglia - the resident immune cells of the central nervous system (CNS). Among the endogenous factors that are capable of regulating microglia activation states, Transforming growth factor β1 (TGFβ1) has been shown to be one of the most potent factors in vivo and in vitro. TGFβ1 immunoreactivity is detectable in midbrain neurons but not in microglia which extend their processes towards TGFβ1-positive midbrain neurons and are located in close proximity to these neurons. This expression pattern suggests, that neuron-derived TGFβ1 might be important to maintain microglia homeostasis under physiological conditions. Indeed, Butovsky and colleagues (2014) have reported that lack of TGFβ1 in the CNS resulted in functional and morphological impairment of microglia. However, it has to be mentioned that the authors used TGFβ1-deficient mice which were crossed to mice expressing TGFβ1 under the control of the IL2-promoter. This approach prevents the lethal postnatal phenotype of TGFβ1-/- mice, which die due to a systemic inflammation mediated by T cells. It remains to be established whether neuron-derived TGFβ1 is essential to mediate microglia maintenance or whether peripheral effects of TGFβ1-deletion are responsible for the microglia phenotype observed by Butovsky et al. (2014).