The role of adaptive immunity in Parkinson's pathology following traumatic brain injury

Abstract

Traumatic brain injury (TBI) increases the risk of Parkinson's disease (PD) development later in life, but the molecular and cellular mechanisms are unknown driving this relationship. A single, mild brain injury can activate both resident and peripheral neuroinflammatory signaling pathways that are similarly activated in the brains of PD patients, likely increasing susceptibility to neurodegeneration. Previous studies have demonstrated that specific subtypes of T cells mediate inflammation in preclinical models of PD in response to the neurotoxic accumulation of alpha synuclein. Certain T cell populations are also known to be activated and recruited to the brain parenchyma at subacute timepoints post-brain injury, and can persist chronically, negatively impacting TBI outcome. Using models of both murine TBI and PD, we evaluated how a pre-existing neuroinflammatory event may exacerbate PD-associated pathologies and behavior. Our transcriptomic analysis of mRNA from purified dopaminergic neurons of mice 90 days post mild TBI (mTBI) revealed upregulation of genes related to neuroinflammation, peripheral immune signaling, and IFN-, in addition to dysregulation of genes known to play a role in PD. Quantification of dopaminergic neurons in the substantia nigra showed significant cell death at 90 days post-injury compared to sham controls, with associated alterations in striatal neurotransmitter levels, like dopamine, leading to behavioral phenotypes. At that same time point, CD8+ T cells are present throughout the brain and around the substantia nigra. When mTBI is induced 30 days prior to induction of PD-associated pathologies via intrastriatal injections of alpha synuclein preformed-fibrils, a similar susceptibility of DA neurons is observed, in addition to an increased severity in alpha synuclein propagation. To examine the role of adaptive immunity in these outcomes, Rag2 KO mice were exposed to the same experimental conditions and displayed significant neuroprotection of the DA neuron population compared to wildtype animals. Taken together, these findings indicate the possibility of a sustained peripheral immune cell infiltration after injury and could support a complex, persistent, and detrimental crosstalk between both resident and peripheral immune cells which negatively affects DA neurons.