Doctor of Philosophy, Case Western Reserve University, 2020, Pathology

Neuronal mitochondrial dysfunction and neuroinflammation are two prominent and potentially etiologic features in neurodegenerative diseases. Despite this, the interplay between both aspects is unclear. Mitofusin 2 (Mfn2) is a GTPase on the outer mitochondrial membrane that promotes mitochondrial fusion, a process essential to mitochondrial health and function. In the present study, we overexpressed Mfn2 exclusively in neurons of mice to augment neuronal mitochondrial fusion in a widely used model of peripheral lipopolysaccharide (LPS)-generated neurodegeneration-associated neuroinflammation. Astonishingly, neuronal Mfn2 overexpression almost completely abolished LPS-induced lethality. These mice further showed alleviation of sickness behavior, bodyweight loss, and ischemic heart pathologies compared to non-transgenic littermates. Moreover, peripheral LPS triggered mitochondrial fragmentation in brain neurons of non-transgenic mice that was completely abrogated by neuronal Mfn2 overexpression. Immunological assays revealed that LPS-induced proinflammatory interleukin (IL)-1β and microglia activation were explicitly reduced in brains and spinal cords of mice with neuronal Mfn2 overexpression. Genome-wide expression analyses identified highly increased expression of microglia inhibitory chemokine CX3CL1 in brains of mice with neuronal Mfn2 overexpression, likely explaining protection from microglia activation and IL-1β-mediated neuroinflammation. To examine the impact of neuronal mitochondrial fusion in a more disease-relevant system, we crossed neuronal Mfn2 overexpression mice with the PS19 tau transgenic mouse model for tauopathy. Excitingly, neuronal Mfn2 overexpression alleviated muscular and cognitive deficits in the model. PS19 mice with neuronal Mfn2 overexpression also displayed a reduction in hippocampal tau pathology and microglia activation compared to tau transgenic mice. In addition, neuronal Mfn2 overexpression reduced abnormal mitochondrial morphologies (open full item for complete abstract)

Committee: Xinglong Wang (Advisor); Brian Cobb (Committee Chair); Shu Chen (Committee Member); Jason Mears (Committee Member); Clive Hamlin (Committee Member) Subjects: Biology; Immunology; Neurosciences; Pathology