Tejaswi Veerati, MS, MPH

Introduction: Parkinson’s Disease (PD) is a movement disorder characterized by resting tremor, bradykinesia, and rigidity¹. There is currently no diagnostic test for PD¹. The neuropathology includes selective loss of dopaminergic neurons in the substantia nigra pars compacta and the deposition of misfolded α-synuclein (α-syn) aggregates in the midbrain¹. Understanding mechanisms for abnormal aggregation of α-syn and the cell death mechanisms mediated by α-syn could lead to a neuroprotective therapy for PD. Methods: C57BL/6 WT and PARP-1 KO mice were used for in vivo intrastriatal injections of α-syn pre-formed fibrils (α-syn-PFF) and NO levels were measured. Lund human mesencephalic (LUHMES) neurons were differentiated to a dopaminergic phenotype and infected with recombinant AAV2 viruses to mediate expression of WT α-syn and mitochondria-tagged α-syn. Mitochondrial ROS quantification and caspase staining was performed. Thioflavin T Fluorescence Assay was performed on human dopaminergic neuroblastoma cells. Western blot analysis was performed on NLRP3 knockout mice. Plasma and CSF were collected from 75 PD patients receiving either 150, 200, 300, or 400 mg of Nilotinib or a placebo. Results: α-syn-PFF induces the activation of PARP-1 and causes PARP-1 mediated cell death of dopaminergic neurons via NO-induced DNA damage². PAR causes a more misfolded, toxic form of α-syn-PFF². Dopaminergic neurons expressing WT α-syn and mitochondria-targeted α-syn had an increase in mitochondrial ROS formation and caspase activation³. Neuronal cells treated with inflammasome activators had truncated α-syn which was reversed with a caspase-1 inhibitor⁴. Further, truncated α-syn generated by caspase-1 is more aggregation-prone⁴. Fibrillar α-syn mediated a delayed activation of the inflammasome pathway in microglia and the presence of caspase-1, IL-1B and ASC⁵. In NLRP3 knockout mice, α-syn could not stimulate release of caspase-1, IL-1B, or ASC from microglia⁵. Soluble TREM2 was increased in CSF of patients treated with 150 mg and 200 mg of Nilotinib⁶. Plasma total α-syn was significantly reduced in the 150 mg group⁶. Conclusions: α-syn-PFF kills dopaminergic neurons via a PARP-1 mediated pathway. Dopaminergic neurons expressing α-syn caused damage to mitochondrial structural/functional and caspase activation. Caspase-1 plays a direct role in the truncation of α-syn, causing aggregation and neuronal cell toxicity. Fibrillar α-syn induces NLRP3 inflammasome pathways driving the neurodegeneration seen in PD through caspase-1 and ASC release. Nilotinib decreases total plasma α-syn and provides an anti-inflammatory effect by triggering TREM2 receptors on myeloid cells. Thus, α-syn is capable of mediating dopaminergic neuron loss via multiple mechanisms, including inflammation and mitochondrial dysfunction.

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