New research from the Baehrecke lab reveals targetable mechanism that drives neurodegenerative disease

 

Mitochondrial dysfunction and neuroinflammation have been implicated in neurodegenerative diseases, but whether these processes are mechanistically linked, and whether they actively contribute to the pathogenesis of neurodegeneration, has remained uncertain.

New research from the Baehrecke lab bridges this gap by demonstrating how mitochondrial dysfunction can initiate neuroinflammation and trigger neuronal cell death, ultimately contributing to neurodegeneration. The work, led by Guangyan Miao, PhD, a postdoctoral researcher in the Baehrecke lab, was recently published in the journal Nature Structural & Molecular Biology.

To carry out the studies, Dr. Miao established a mouse model for neurodegeneration caused by mitochondrial impairment. She generated mice with a conditional knockout of Vps13d, a conserved gene important for regulating mitochondrial morphology and selective autophagic mitochondria clearance, or mitophagy. Mutations in the human VPS13D gene have been linked to several neurodegenerative disorders, including a spectrum of movement disorders such as spinocerebellar ataxia and spastic ataxia.

Dr. Miao and colleagues found that mice with a conditional Vps13d knockout in excitatory projection neurons displayed multiple behavior defects—including impaired locomotor activity, coordination, learning and memory—as well as age-related neuronal cell death in the hippocampus. They then used this mouse model to explore the cellular and molecular responses that contribute to neuronal loss.

Their work revealed that hippocampal neurons lacking Vps13d accumulate damaged mitochondria, leading to activation of gasdermin E (GSDME), an effector of a pro-inflammatory form of cell death called pyroptosis. During pyroptosis, GSDME forms transmembrane pores, causing the release of cellular contents. They found that activation of GSDME leads to release of mitochondrial DNA and activation of the DNA-sensing cGAS-STING pathway, a key mediator of inflammation. In turn, cGAS-STING signaling promotes activation of microglia—immune “sentinel” cells in the brain that orchestrate a potent inflammatory response—which contributes to neuronal cell death. Previous studies have shown that activated microglia promote the release of a variety of inflammatory and neurotoxic mediators (including cytokines, proteases and superoxide) to induce neuronal cell death.

They further demonstrated that depletion of microglia (using a highly selective brain-penetrant inhibitor of CSF1R signaling, which is required for microglial survival) suppressed neuronal loss and behavioral defects, demonstrating that microglia play a key role in neuronal cell death in this model of neurodegenerative disease. Genetic or pharmacologic inhibition of GSDME also improved neuronal survival and reduced microglial activation.

Therapeutic implications

Identifying the order in which cellular and molecular changes occur in neurodegeneration is crucial for developing targeted treatments that can mitigate neuronal loss. A key result of this study is that mitochondrial dysfunction, mitophagy defects, neuroinflammatory changes and microglial activation all arise prior to neuronal cell death—highlighting several potential points for therapeutic intervention.

The findings contribute to the body of evidence supporting the development of mitophagy enhancers as a therapeutic approach for neurodegenerative diseases. Notably, small molecules that selectively enhance mitophagy are entering phase I clinical trials. Furthermore, the results support the notion that blocking GSDME and/or downstream cGAS-STING signaling may hold therapeutic potential for VPS13D-associated neurodegenerative disorders.

Discovery driven by collaboration

Research in Dr. Baehrecke’s lab centers on autophagy, and he attributes the success of this multidisciplinary project to strong teamwork with colleagues across UMass Chan specializing in mouse genetics, neurobiology, and innate immunity and inflammation.

We could not have done this without the strong support of Junhao Mao, who contributed his expertise in mouse genetics, Dorothy Schafer, whose expertise in neuroinflammation and microglia was instrumental to the project, and Katherine Fitzgerald, who provided critical insight into cGAS-STING signaling,” said Dr. Baehrecke.