Efforts to reduce the personal and societal burden of neurodegenerative disease (ND) hinge on the identification of the underlying molecular mechanism(s) that causes neuronal death. One common aspect of neuronal death in Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD) is the relationship to the buildup of neurotoxic proteins. Glial cells, normally neuroprotective, can be transformed into a neuroinflammatory state (“A1” for astrocytes) stimulated by this neuronal detritus and by microglial activation. Interestingly, pathological mitochondrial fission mediated by Drp1-Fis1 interaction (as opposed to physiological fission through Drp1-Mff) is also a characteristic of many ND. In their new study, Joshi et al. used various mouse ND models to reveal a process where microglia expressing neurotoxic proteins released dysfunctional and fragmented mitochondria that drove A1 astrocyte-triggered neuroinflammation and subsequent innate immune-mediated neuronal death, with the resultant debris contributing to additional inflammation. Importantly, disruption of the Drp1-Fis1 interaction ameliorated these effects. The authors stressed that the fate of neurons was determined by the extracellular ratio of damaged to normal mitochondria, which was dependent on the amount of pathological fission in microglia. Together, the results suggest that inhibition of Drp1-Fis1-mediated mitochondrial fission, with the goal of increasing the ratio between functional and damaged mitochondria, may offer a new approach to neuroprotection in various NDs.

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Reference

1. Joshi et al. Nat Neurosci. 2019 Oct;22(10):1635-1648.