Objective/Rationale:
Microglia, one of the key players in neuroinflammation, are increased in number and activated in the brains of Parkinson’s disease (PD) or pre-clinical models of PD. A recent study demonstrated a correlation on the level of fractalkine, the only known chemokine that is highly expressed in neurons, with PD disease severity as well as PD progression, compared to healthy and diseased controls. Here we hypothesize that microglial activation via fractalkine-its receptor (CX3Cr1) signaling pathway plays an important role in neuronal dysfunction and neuronal cell death in PD. We further hypothesize that regulating this signaling pathways will effectively modulate disease progression, thereby providing a novel therapeutic target in PD treatments.
Project Description:
Using transgenic pre-clinical models expressing normal and mutated (A53T) human alpha-synuclein, we will quantitatively analyze the expression pattern and level of fractalkine in the cerebrospinal fluid (CSF) and different brain regions at different ages. In parallel, we will use an invasive, long-term in vivo (two-photon) imaging technique to study microglia motility and microglial interaction with neuronal components, including cell body, axon, dendrites and synapses in response of alpha-synuclein expression. Furthermore, we will also monitor whether the microglia-neuron interaction may be modulated after treatments with pro- or anti-inflammatory agents.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Microglia, the primary immune effecter cells in the brain, dynamically extend or retract their processes and actively survey the microenvironment in normal as well as diseased conditions. Evidence suggests that microglia are activated in neurodegenerative disorders, including PD. A positive correlation of fractalkine level with PD progression/severity has been observed. This project will try to mimic a situation in which pre-clinical models express normal or mutated alpha-synuclein, similar to humans, to investigate whether this phenomenon is also true in pre-clinical models of PD. The study may reveal novel therapeutic targets for modulating PD progression.
Anticipated Outcome:
We anticipate that the information obtained in the study will shed light on the roles of microglial activation and microglia-neuron interaction via fractalkine and its receptor in PD pathogenesis. Additionally, it may also provide a clue for the potential therapeutic targeting fractalkine and its receptor signaling in PD pathogenesis as well as treatment.
Progress Report
Microglia are key players in neuroinflammation and are increased in number and activated in the brains of Parkinson’s disease (PD) and pre-clinical models of PD. Here, we have used two lines of transgenic models expressing human wildtype a-synuclein or human A53T a-synuclein, respectively, and AAV viral transducing human a-synuclein to study levels of fractalkine and its receptor (CX3Cr1) and also microglial dynamics in response to a-synuclein expression. We demonstrated that transgenic models expressing human wt a-synuclein or mutated A53T a-synuclein do not develop significant motor deficits (rotarod tests) by one year old and that density of microglia appears similar between transgenic models and their wildtype non-carrier models at different ages. Only in old aged A53T models it appears that microglia is more activated (more processes) compared to the wildtype ones. Very interestingly, after we transduced AAV vector expressing human wildtype a-synuclein in adult cortex that express CX3Cr1-GFP, as microglial marker. Using in vivo two photon imaging technique we found that the AAV-transduced-a-synuclein expression induces significantly increased microglia mobility and migration, in the ipsi- and contra-lateral sides of the injection. Furthermore, AAV-transduced-a-synuclein expression induces microglial activation from resting state to amoeboid-like state. The data indicates the direct correlation between microglia activation and a-synuclein expression and further our understanding on the role of microglia in neuroinflammation in a-synuclein expression conditions.
Presentations & Publications
A manuscript regarding in vivo imaging microglia activation and a-synuclein expression is in preparation.
December 2012