Vision Rewired: John Flanagan on Axonal Regeneration
“The loss of connections between cells of the central nervous system (CNS) is a devastating problem that currently has no effective treatment,” said John Flanagan, who gave the third lecture in the NEI Audacious Goals Initiative Seminar Series in Neuroregeneration. Flanagan, who is a professor of cell biology at Harvard Medical School, told the audience he believes that will change in the coming years, yielding potential therapies for a host of neurological and vision disorders.
“Axons are not inherently incapable of regenerating,” he said, citing evidence that includes studies of frogs and other amphibians who do it naturally. Axons are the nerve fibers that carry signals from one cell to another. Eye diseases like glaucoma can degrade axons that extend from the retina to the brain via the optic nerve. Whereas a frog can regain visual function after its optic nerve has been cut; humans and other mammals cannot. For years, scientists have tried to learn why.
Neurons with severed axons can survive for years; however, proteins called chondroitin sulfate proteoglycans (CSPGs) that appear at sites of injury prevent these cells from re-growing and reconnecting their axons to appropriate targets. How CSPGs did this was unknown for many years. Work by Flanagan has helped elucidate how CSPGs exert their effects, showing they bind to a receptor protein on neurons called protein tyrosine phosphatase sigma (PTPσ). But curiously, PTPσ also binds to heparin sulfate proteoglycans (HSPGs), molecules that promote axonal growth. So how could activating the same signaling pathway render an opposite effect?
Flanagan and collaborators found that HSPGs cause clustering of PTPσ receptors; CSPGs do not. And it’s this clustering, according to Flanagan, that probably launches a signaling cascade toward axonal growth. “PTPσ acts as a ligand-dependent switch.” Function is dictated by the type of molecule binding with the receptor. Both HSPGs and CSPGs are present in the CNS. And so it’s the HSPG/CSPG ratio that controls the action—axonal growth or inhibition—of PTPσ. Flanagan is now exploring whether boosting the ratio toward HSPG can treat CNS injuries.
Of great interest to the NEI Audacious Goals Initiative (AGI), Flanagan’s work could have implications for optic nerve regeneration. The AGI is a sustained effort to catalyze vision research. Central to the AGI is the goal of restoring vision through regeneration of neurons and neural connections in the eye and visual system, which are affected by not only glaucoma but also other common eye diseases such as age-related macular degeneration and diabetic retinopathy. Today, when these diseases advance to the point of damaging neural connections, vision loss is almost always irreversible.
“Is restoring these connections an achievable goal?” queried Flanagan. An emphatic yes was his answer.