Role of alpha-synuclein in glial cells

Human alpha-synuclein is an 140 amino acids protein normally localized in the presynaptic terminals of neurons. Recently, a-synuclein has been detected in the pathological protein aggregations in several neurodegenerative diseases often named alpha-synucleinopathies. Interestingly, alpha-synuclein which is normally not found in glial cells of the healthy brain, has been observed in glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA) as well as in glial cells of Parkinson`s disease(PD) and dementia with Lewy bodies (DLB) brains. Yet, its role for the neurodegenerative process and glial biology remains unclear. In the present proposal, based on our previous experience, we focus on the effects of alpha-synuclein overexpression in oligodendroglial cells in respect to the mechanisms of protein inclusion formation and its role for the survival and vulnerability of the cells. In the first experiment we intend to transfect primary oligodendroglial cells and oligodendroglioma cell lines with vectors encoding full length or C-terminally truncated alpha-synuclein and study the cellular morphology and mechanisms of cell death. In a second set of experiments we will test the role of oligodendroglial expression of alpha-synuclein for the interactions with neurons in a co-culture system. Further, we will test the role of external factors, namely proinflammatory cytokines such as tumor necrosis factor alpha and several neurotrophins, that might participate in the pathogenesis of neurodegenerative diseases, for inclusion formation and survival of oligodendroglial and neuronal cells overexpressing alpha-synuclein as well as their effects in co-culture. We consider that the proposed experiments will give basic information on the role of alpha-synuclein for glial biology and glial-neuronal interactions and might be of further importance for understanding the pathogenesis of alpha-synucleinopathies.

Human alpha-synuclein is a 140 amino acids protein normally localized in the presynaptic terminals of neurons. Recently, alpha-synuclein has been detected in the pathological protein aggregations in several neurodegenerative diseases therefore named alpha-synucleinopathies including Parkinson`s disease, multiple system atrophy and dementia with Lewy bodies. Parkinson`s disease is one of the most frequent neurodegenerative diseases affecting 1- 2% of the general population above 65 years. Approximately 5% of all patients with Parkinson`s disease will develop multiple system atrophy, a severe and rapidly progressive neurodegenerative disorder leading to death in about 8 years. Interestingly, alpha-synuclein, which is normally not found in glial cells of the healthy brain, has been observed in glial cytoplasmic inclusions in multiple system atrophy as well as in glial cells of Parkinson`s disease and dementia with Lewy bodies brains. Yet, its role for the neurodegenerative process and glial biology remains unclear. In our project we have analyzed the effects of alpha-synuclein overexpression, particularly the formation of insoluble protein aggregates, cellular morphology and mechanisms of cell death in oligodendrocytes and the consequences of glial expression of alpha-synuclein on the interaction of glial and neuronal cells. We have developed a novel animal model of multiple system atrophy to study the consequences of oligodendroglial expression of alpha-synuclein in transgenic mice. Using this transgenic mouse model we could demonstrate that intracellular alpha-synuclein inclusions in oligodendrocytes increase the vulnerability of neuronal cells to oxidative stress. The neuropathology of this model corresponds exactly to the human disease multiple system atrophy. Further, we could demonstrate that oligodendroglial overexpression resulted in a broad activation of microglial cells and neuroinflammation, which led to increased neuronal cell damage. Suppression of microglial activation by long-term minocycline treatment exerts neuroprotection. Furthermore, we identified molecules of the innate immune response signal as key signal transducing receptors and confirmed these findings in pathological specimen of patients with multiple system atrophy. In conclusion our results represent new perspectives in terms of studies on the pathogenesis and therapeutic approaches of multiple system atrophy.