Project Summary
The nervous system was traditionally thought to act independently of an organism’s immune response and be
an “immune privileged site”. Increasing scientific evidence has shown that the nervous system is not immune
privileged but instead has a unique immune response that is critical for maintaining homeostasis and critical for
central nervous system (CNS) function. Much of the work in the field of neuroinflammation has focused on the
function of microglia, but little is known about the role of neurons in modulating neuroinflammatory responses
in the CNS. Five years ago, we discovered that the neuronal protein, alpha-synuclein(asyn), was critical in
protecting neurons from viral infection. We have extended these data to show that ayn modulates type 1
interferon (T1IFN) signaling. Asyn is known as a cause of Parkinson’s disease (PD) and is known to be
dysregulated in neurodegenerative diseases, traumatic brain injury, and other diverse CNS diseases. Despite
the importance of asyn in CNS disease states, the functional role of asyn expression is not well understood.
We have discovered that asyn expression is necessary to support expression of specific interferon stimulated
genes (ISGs) in the brain during T1IFN signaling, independent of microglia activation. Using induced
pluripotent stem cells (iPSC) and CRISPR-mediated SNCA deletion to create asyn KO human dopaminergic
neurons, we found that viral growth in neurons is inhibited in the presence of asyn expression and that viral-
induced ISGs such as IFIT1, OAS1, and TRIM25 exbibit decreased expression in asyn KO neurons. We next
found that asyn KO neurons exhibit a broad loss of ISG expression following treatment with poly I:C or type 1
interferon (¿2) treatment due to loss of asyn-dependent STAT2 activation and asyn nuclear localization. Taken
together, our data show for the first time that asyn functions to support interferon responses in neurons. The
goal of this proposal is to determine the specific mechanism of asyn-dependent innate immune responses in
neurons. We hypothesize that asyn is a novel neuron-intrinsic regulator of the CNS innate immune response.
We will test our hypothesis in three aims. Aim 1 will use asyn KO and WT human neurons to define the specific
interactions between asyn, interferon signaling, and vesicle transport in neurons. Aim 2 will define the role of
neuron-intrinsic asyn production on the innate T-cell response in the brain using an inducible, nestin-Cre-lox
knockout of the asyn gene (Snca) in mice. Aim 3 will evaluate PD-specific and species specific changes in
asyn that may influence its native function in neurons. Taken together, the proposed studies will significantly
advance our understanding of neuron-intrinsic control of the innate immune response in the CNS and provide
novel insight into the underlying immunopathogenesis that contributes to diverse human diseases of the CNS.
