MSA and Neuroinflammation

Multiple system atrophy (MSA) is a neurodegenerative disorder that occurs sporadically and causes parkinsonism, cerebellar, autonomic, urinary and pyramidal dysfunction in many combinations. The pathogenesis of the disease remains largely unknown. Oligodendroglial cytoplasmic inclusions (GCIs) are observed throughout the cortico- striato-pallido-cortical loops and may contribute to the basal ganglia dysfunction. Several efforts have been made in the last decade to model the neuropathology of MSA. We have recently described the first mouse model of MSA that reproduces the key features of MSA glial and neuronal pathology by combining transgene and neurotoxin approaches. In this novel murine model we have observed MSA-like pathology including striatonigral degeneration and olivopontocerebellar atrophy accompanied by alpha-synuclein oligodendroglial inclusions, microglial activation and astrogliosis. The MSA mouse model represents a powerful tool to dissect the pathogenesis of the human disease. For example, we recently detected toll-like receptor 4 (TLR4) up-regulation in microglia of transgenic MSA mice. These changes were also observed in human MSA brains. In the present project we will study the role of innate immune mechanisms for microglial activation induced by alpha-synuclein. We will address this issue parallel in in vitro co-culture studies combined with FACS analysis and in in vivo cross-breeding studies of alpha-synuclein transgenic and TLR4 deficient mice combined with behavioural and neuropathological analysis. These experiments are expected to reveal new insights into the pathogenesis of this devastating neurodegenerative disorder and pave the way towards new therapeutic approaches for the human disease MSA.

Multiple system atrophy (MSA) is a neurodegenerative disorder that occurs sporadically and causes parkinsonism, cerebellar, autonomic, urinary and pyramidal dysfunction in many combinations. Alpha-synuclein positive oligodendroglial cytoplasmic inclusions are observed throughout the cortico-striato-pallido-cortical loops and may contribute to the basal ganglia dysfunction. The neurodegeneration is accompanied by neuroinflammation which may further mediate the neuronal loss, however the exact pathogenesis of the disease remains largely unknown. At present the disease lacks efficient therapy, progresses rapidly and leads to early disability and death. In this project we applied a transgenic mouse model of MSA that reproduces key features of MSA glial and neuronal pathology as well as in vitro cell culture model of alpha-synucleinopathy to address the role of toll-like receptor 4 (TLR4), an innate immunity receptor, in the pathogenic cascade of MSA and define its possible role as a therapeutic target. Our experiments showed reduced phagocytosis and suppression of TNF-alpha production in TLR4-deficient microglia activated by fibrillar alpha-synuclein in vitro. However, the ablation of TLR4 in a transgenic mouse model of MSA-like alpha-synucleinopathy augmented motor disability and the underlying loss of nigrostriatal dopaminergic neurons and terminals. TLR4 deficiency in transgenic mice with alpha-synuclein overexpression led to increased accumulation of alpha-synuclein in the brain. Furthermore, TLR4 ablation in a transgenic alpha- synucleinopathy mouse model led to increased TNF-alpha levels in midbrain, associated with enhanced pro- inflammatory signaling by astroglia. These research data define for the first time TLR4 signaling in alpha- synucleinopathies as a natural endogenous neuroprotective mechanism that mediates the clearance of alpha- synuclein and may contribute to the dual role of neuroinflammation in these neurodegenerative disorders. The experiments reveal new insights into the pathogenesis of alpha-synucleinopathies and provide novel insights towards new therapeutic approaches for the human disease MSA.