Scientists Reveal a Molecule That May Underpin Neurological Disorders


Source: University of Tokyo

Summary: Researchers have identified a molecule that aids a crucial “pruning” process in the brain that, if malfunctioning, could lead to disorders such as autism and dementia.


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, weaker branches are discarded to redirect nutrients to help nurture the stronger branches. However, genetic and environmental 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. Researchers from the University of Tokyo have identified a molecule that aids a crucial “pruning” process in the brain that, if malfunctioning, could lead to disorders such as autism and dementia. The study findings were published in the journal Neuron.

Retrograde Signaling from Progranulin to Sort1 Counteracts Synapse Elimination

Progranulin derived from Purkinje cells (PCs) counteracts synapse elimination and reinforces the strongest (winner) climbing fiber (CF). Progranulin acts on developing CF synapses from Postnatal day 11 to 16 independently of Semaphorin3A, another retrograde signaling molecule that counteracts CF synapse elimination. Progranulin derived from PCs acts retrogradely onto its putative receptor Sort1 on CFs. Loser CFs are maintained by progranulin-Sort1 signal and Semaphorin3A-PlexinA4 signal, but they are eventually pruned by “elimination signals” such as Semaphorin7A and brain-derived neurotrophic factor (BDNF). Credit: Masanobu Kano

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. The research 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. Researchers feel that progranulin signaling may be a potential therapeutic target for neuropsychiatric disorders.

Prof. Masanobu Kano said, “Our results provide a new insight into the roles of progranulin in the developing brain”, “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.”


More Information: Naofumi Uesaka et al, “Retrograde Signaling from Progranulin to Sort1 Counteracts Synapse Elimination in the Developing Cerebellum”, Neuron (2018). DOI: 10.1016/j.neuron.2018.01.018


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