NIH Research Festival
Hereditary spastic paraplegia (HSP) is a rare genetic disorder causing lower limb spasticity and paralysis in young children and progressing throughout adulthood. Classically defined as a motor neuron disease, the source of paralysis remains unknown. Here, were present the novel hypothesis that trophic support from myelinating glial cells, termed oligodendrocytes, contributes to HSP pathophysiology. In patients, mutations to autophagy-related protein Adaptor Protein 4 (AP-4) are frequently associated with HSP. Most recently, it has been found that AP-4 facilitates normal autophagy through the translocation of autophagy-related gene 9A (ATG9A) and notably, AP-4 KO animals display a thin myelin corpus callosum. To investigate the previously unexamined role of oligodendrocytes in HSP, we induced autophagy in wild-type oligodendrocyte progenitor cells. Our preliminary data reveals expression of autophagy pathway related proteins AP-4, ATG9A, and microtubule-associated protein 1A/1B-light chain 3 (LC3B) in oligodendrocyte progenitor cells following hypoxia and glucose starvation. Further, we present data suggesting autophagy is active during normal oligodendrocyte maturation and development in vitro. These findings indicate autophagy is an important, but largely overlooked, function in oligodendrocyte development, maturation, and myelination of axons. These studies will ultimately provide insight into our understanding of HSP and potential new interventions for patients.
Scientific Focus Area: Neuroscience
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