A molecule known as progranulin, which aids a crucial “pruning” process in the brain that, if malfunctioning, could lead to disorders such as autism and dementia, has been identified by scientists from Japan. The research team was led by Masanobu Kano, professor in the Department of Neurophysiology at the Graduate School of Medicine at the University of Tokyo.

As the brain develops in utero and in early life, neurons and their connecting synapses branch out rapidly, like a tree. Over time, these connections become more refined and purposeful via a series of molecular mechanisms that prune the connections.

Just as a gardener trimming a tree, weaker branches are discarded to redirect nutrients to help nurture the stronger branches.

However, environmental and genetic mutations can misguide this process and eliminate far too many synapses or not nearly enough. Either extreme can result in a myriad of neuropsychiatric disorders from autism spectrum disorder to schizophrenia to dementia.

Progranulin And Climbing Fibers

In a typically developing brain, a type of neuron called a Purkinje cell is furnished with climbing fibers.

“Among multiple climbing fibers innervating each Purkinje cell in the neonatal cerebellum, a single climbing fiber is strengthened and maintained throughout an animal’s life, whereas the other climbing fibers are weakened and eventually eliminated,” Kano says. “Our goal was to identify a new molecule involved in strengthening and maintaining single climbing fiber inputs."

Kano and his team found that progranulin — a protein known to be involved in certain forms of dementia — also works to maintain developing climbing fiber inputs, counteracting the initial elimination. They studied a mouse model engineered without progranulin and found that climbing fibers were more quickly eliminated and climbing fiber input overall was significantly reduced.

“Our results provide a new insight into the roles of progranulin in the developing brain,” says Kano. “We will continue to search molecules involved in synapse elimination in the developing cerebellum and, ultimately, we want to elucidate entire signaling cascades for synapse elimination."

Although the researchers do not yet know how to effectively manipulate the molecule, it’s possible that progranulin signaling may be a potential therapeutic target for neuropsychiatric disorders.

Uesaka, Naofumi et al. Retrograde Signaling from Progranulin to Sort1 Counteracts Synapse Elimination in the Developing Cerebellum Neuron, DOI: https://doi.org/10.1016/j.neuron.2018.01.018

Image: Mouse Cerebellum with Purkinje cells (calbindin, green) and Basket cells (Neurofilament, red) . Nuclei are blue (DAPI).

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