Neuronal Dysfunction and Behavioral Abnormalities Are Evoked by Neural Cells and Aggravated by Inflammatory Microglia in Peroxisomal β-Oxidation Deficiency

Abstract

It is becoming evident that microglia, the resident immune cells of the central nervous system (CNS), are active contributors in neurological disorders. Nevertheless, the impact of microgliosis on neuropathology, behavior and clinical decline in neuropathological conditions remains elusive. A mouse model lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, develops a fatal disorder characterized by motor problems similar to the milder form of human disease. The molecular mechanisms underlying neurological decline in men and mice remain unknown. The hallmark of disease in the mouse model is chronic proliferation of microglia in the brain without provoking neuronal loss or demyelination. In order to define the contribution of Mfp2−/− neural cells to development of microgliosis and clinical neuropathology, the constitutive Mfp2−/− mouse model was compared to a neural selective Nestin-Mfp2−/− mouse model. We demonstrate in this study that, in contrast to early-onset and severe microgliosis in constitutive Mfp2−/− mice, Mfp2+/+ microglia in Nestin-Mfp2−/− mice only become mildly inflammatory at end stage of disease. Mfp2−/− microglia are primed and acquire a chronic and strong inflammatory state in Mfp2−/− mice whereas Mfp2+/+ microglia in Nestin-Mfp2−/− mice are not primed and adopt a minimal activation state. The inflammatory microglial phenotype in Mfp2−/− mice is correlated with more severe neuronal dysfunction, faster clinical deterioration and reduced life span compared to Nestin-Mfp2−/− mice. Taken together, our study shows that deletion of MFP2 impairs behavior and locomotion. Clinical decline and neural pathology is aggravated by an early-onset and excessive microglial response in Mfp2−/− mice and strongly indicates a cell-autonomous role of MFP2 in microglia.

The peroxisome: an update on mysteries 2.0

“…The nestin–MFP2 −/− mouse showed the most severe pathology establishing a locomotor phenotype comparable to the constitutive MFP2 knockout. Early on the mice develop a progressive ataxia, kyphosis and abnormal limb positioning; however, they also exhibit a prolonged life and generally less severely altered neurologic parameters than the full knockout (Verheijden et al 2013 ; Beckers et al 2018 ). Morphologically, the neural phenotype was accompanied by cerebellar atrophy with early-onset axonal swellings and a dramatic reduction in Purkinje cells at an age of 1 year.…”

“…Morphologically, the neural phenotype was accompanied by cerebellar atrophy with early-onset axonal swellings and a dramatic reduction in Purkinje cells at an age of 1 year. Both, the total and the neural MFP2 knockouts developed an inflammatory brain phenotype, which, however, differed significantly in its severity (Verheijden et al 2013 ; Beckers et al 2018 ). The authors concluded that the initial primary neuronal deficits are exaggerated by the strong microglia activation only found in the constitutive MFP2 −/− mice (Beckers et al 2018 ).…”

“…Both, the total and the neural MFP2 knockouts developed an inflammatory brain phenotype, which, however, differed significantly in its severity (Verheijden et al 2013 ; Beckers et al 2018 ). The authors concluded that the initial primary neuronal deficits are exaggerated by the strong microglia activation only found in the constitutive MFP2 −/− mice (Beckers et al 2018 ). Unexpectedly, the deletion of MFP2 from oligodendrocytes (Cnp–Pex5 −/− ) resulted in a rather mild phenotype without signs of ataxia and inflammatory responses before 12 months of age.…”

Metabolic Reprogramming during Microglia Activation

“…Twelve-week old control mice were injected intraperitoneally with 100 µL LPS (1 mg/kg, Sigma Aldrich, St. Louis, MO, USA or sterile saline as previously reported [39,40]. After 4 h, mice were sacrificed and brains were snap frozen in liquid nitrogen and stored at −80 °C.…”

Aging lowers PEX5 levels in cortical neurons in male and female mouse brains

“…For one, deleting the MFP2 peroxisomal enzyme (which is responsible for β-oxidation) in mouse microglia, switched their state to a proinflammatory one, but this change did not affect neuronal health or the microglial response to injury (Beckers, Geric et al 2019). Another study looked at a neuron-specific form of MFP2 deletion, and discovered that unlike constitutive Mfp2 -/knockouts, Nestin-Mfp2 -/knockout brains possessed microglia that were not primed for an inflammatory response (Beckers, Stroobants et al 2018). Microglial peroxisomal dysfunction, as seen in a microglial model deficient in acyl-coA oxidase 1 (ACOX1), has also been shown to affect catalase activity, the peroxisome, lipid droplet and mitochondrial number in microglia, as well as the induction of interleukin-1β (IL-1β), the repression of interleukin-6 (1L-6) and the increased expression of Trem2, which codes for a cell surface protein that plays a role in microglial phagocytosis (Raas, Saih et al 2019).…”