Final Report Summary - DIABLO (Mechanisms of Developmental and Injury-related Axon Branch Loss)
The overarching goal of the DIABLo project was to explore the subcellular (i.e. cell biological and molecular) mechanisms of axon loss in the developing and diseased mammalian nervous system. Axon loss not only sculpts neuronal networks in development, but also occurs early in numerous neurological diseases. Indeed, the lifetime risk for diseases with an “axonopathic” component approaches 50%. Pathological axon loss likely involves aberrant activation of developmental programs – just as cell death in disease often takes the form of apoptosis, another prominent regressive event in neural development. Over the past few years, the first molecular pathways have emerged for one form of axon loss, Wallerian degeneration, which removes entire axon arbors after severing. However, Wallerian degeneration is of limited clinical significance – because the axon is cut and hence incapacitated before it is lost – and appears to play only minor roles in development. In contrast, “non-Wallerian” forms of axon loss that selectively remove individual “aberrant” branches dominate during development (“axon branch loss”). Due to the technical challenge of studying axon loss in the complex environment of the developing mammalian nervous system, the subcellular events that precede such non-Wallerian forms of axon branch loss are poorly understood, even though this phenomenon – when pathologically reactivated – likely contributes to axonal pathology in many neurological disorders. The DIABLo project, through development of new imaging modalities and their application developmental and disease-related settings of non-Wallerian axon loss has now revealed a number of new and surprising insights:
(1) We discovered that during development of motor neurons, individual branches of the neuron’s axonal arbor can be selectively dismantled by local loss of the microtubular cytoskeleton that normally stabilizes axons. This is mediate by an enzyme, spastin, which cuts microtubules, but is also mutated in some forms of neurodegenerative diseases. The activity of spastin appears to be locally regulated by posttranslational modifications along the microtubules. Importantly, this process not only regulates axon stability but also an axon’s signalling to neighboring glial cells in order to regulate the onset of myelin formation.
(2) Mechanisms of axon loss appear to be shared between development and disease and across diseases. For instance, microtubule loss also appears to be an early event in the damage to axons in a specific form of neuroinflammation, where autoantibodies locally destroy astrocytes, an important class of glial cells. Similarly, the formation of nanoscale membrane defects appears to be a shared feature between neuroinflammatory axon loss and traumatically induced axon pathology.
Together, these results provide fundamental insights into the biology of axons, the potential to ameliorate axon loss by targeting subcellular pathology and the risks of interfering with normal development or reparative remodeling.
(1) We discovered that during development of motor neurons, individual branches of the neuron’s axonal arbor can be selectively dismantled by local loss of the microtubular cytoskeleton that normally stabilizes axons. This is mediate by an enzyme, spastin, which cuts microtubules, but is also mutated in some forms of neurodegenerative diseases. The activity of spastin appears to be locally regulated by posttranslational modifications along the microtubules. Importantly, this process not only regulates axon stability but also an axon’s signalling to neighboring glial cells in order to regulate the onset of myelin formation.
(2) Mechanisms of axon loss appear to be shared between development and disease and across diseases. For instance, microtubule loss also appears to be an early event in the damage to axons in a specific form of neuroinflammation, where autoantibodies locally destroy astrocytes, an important class of glial cells. Similarly, the formation of nanoscale membrane defects appears to be a shared feature between neuroinflammatory axon loss and traumatically induced axon pathology.
Together, these results provide fundamental insights into the biology of axons, the potential to ameliorate axon loss by targeting subcellular pathology and the risks of interfering with normal development or reparative remodeling.