We are studying the cell-autonomous and non-cell-autonomous mechanisms of axon degeneration, a process akin to programmed cell death. Degeneration of axons is a hallmark in many neurodegenerative conditions including those associated with abnormal glia. Thus, we have great hopes that understanding why and how axons degenerate may lead to more efficient neuroprotective therapies tailored to specifically support axons and their surrounding glia.
Axons are the longest cellular projections of neurons relaying electrical and biochemical signals in nerves and white-matter tracts of the nervous system. As such, they are critical for neuronal wiring and transport of neuronal maintenance signals. Axons do not exist in isolation, but are inextricably and intimately associated with their enwrapping glia (Schwann cells and oligodendrocytes) to form an unique axon-glia unit.
Because of their incredible length and energetic demand (human motor neurons can be one meter long), axons are very vulnerable and at continuous risk of damage. Many debilitating neurodegenerative disorders share the common feature of early damage and demise of axons. The most relevant neurological symptoms in a number of these conditions are due to compromised axon integrity. Thus, neuroprotective therapies promoting axon stability have great potential for more efficient treatment. Our laboratory is investigating the cell-autonomous and non-cell-autonomous mechanisms of the degeneration of axons. In other words, we are attempting to elucidate what causes axon breakdown from within neurons, and which external (glial) events trigger axon loss.
Recent studies indicate that axonal degeneration, at least in experimental settings, is an active and highly regulated process akin to programmed cell death ('axonal auto-destruction'). Moreover, it is increasingly realized that axonal maintenance relies not only on neuron-derived provisions but also on trophic support from their enwrapping glia. The mechanism for this non-cell-autonomous support function remain unknown, but emerging evidence indicates that it is distinct form the glial role to insulate axons with myelin. We are pursuing the intriguing question whether abolished support by aberrant delivery of metabolites and other trophic factors from glia into axons is mechanistically linked to the induction of axonal auto-destruction. This concept is supported by our recent finding that metabolic dysregulation exclusively in Schwann cells is sufficient to trigger axon breakdown.
Dr. Bogdan Beirowski is an Assistant Professor with the Hunter James Kelly Research Institute and in the Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo.
Dr. Elisabetta Babetto is a Research Assistant Professor with the Hunter James Kelly Research Institute and in the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo.
The long-term maintenance of a healthy neuronal population with their intricate wiring is a formidable challenge. Neurons are unable to restore their number by cell division after an insult, and are particularly susceptible to injury due to their peculiar cytoarchitecture with meter-long axons.
Many neurodegenerative conditions result in the early loss of axonal connectivity. Muscle wasting, paralysis and neuropathic pain are prime examples of the symptomatic consequences in the peripheral nervous system. The clinical relevance and widespread incidence of axon demise prompts the question of how axons degenerate and how we can manipulate the rate of axon loss, as well as restore connectivity by exploiting axonal plasticity. Also, much remains to be done to shed more light on the driving forces of axon loss. In this respect, enwrapping glia and macrophages regulate axon integrity both physiologically and after injury, but very little is known about which pathways orchestrate axon survival non-cell-autonomously. Dr Babetto's studies focus on these key questions with the hope to translate her findings, one day, in therapeutic tools.
View all of Dr. Beirowski’s publications on PubMed.