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UMMS discovery uncovers nesprin ‘railroad tracks’ from nucleus to synapse that direct RNA localization

Findings provide new insights into mRNA transport for local translation at postsynaptic sites.

By Jim Fessenden

UMass Medical School Communications

June 24, 2015
  Vivian Budnik, PhD
  Vivian Budnik, PhD

Researchers at UMass Medical School have pinpointed a novel mechanism responsible for the long-range transportation of RNA from the nucleus of muscle cells to developing postsynaptic sites along the neuromuscular junction, according to a study published in Neuron. The discovery sheds new light on the assembly and modification of the postsynaptic apparatus during developmental synaptic growth and activity-dependent plasticity. It also provides a new avenue of investigation for a variety of musculoskeletal disorders such as X-linked Emery–Dreifuss muscular dystrophy and cerebellar ataxia.

“An important mechanism underlying synapse development and plasticity is the localization of messenger RNAs (mRNA) that travel from the nucleus to the synaptic sites,” said Vivian Budnik, PhD, Worcester Foundation for Biomedical Research Chair, and chair and professor of neurobiology. “We’ve demonstrated that the giant nuclear-associated Nesprin1 protein forms striated F-actin-based filaments, which we dubbed ‘railroad tracks,’ that span from muscle nuclei to postsynaptic sites.”

These railroad tracks wrap around immature boutons – the knoblike presynaptic structures of axons at the neuromuscular junction—present during development or in response to new stimuli. Messenger RNAs packaged into granules inside the muscle cell nucleus are transported along the Nesprin1 railroad tracks all the way to these immature boutons where they are then translated into proteins needed for post-synaptic development and function, leading to maturation of the synaptic bouton.

Dr. Budnik and colleagues showed that in the absence of the Nesprin1 protein, mRNAs were unable to reach their intended destination, instead accumulating around the nucleus. This resulted in an accumulation of immature boutons lacking postsynaptic proteins needed for plasticity.

The study suggests an important mechanism by which RNAs are transported specifically to sites of postsynaptic maturation. “In particular, we have uncovered a novel pathway which serves as a long-range path for mRNA localization and synapse maturation,” said Budnik. This study is of significant importance because, in addition to its role in several musculoskeletal disorders, Nesprin1 is further associated with bipolar disorder, and is a risk gene for schizophrenia and autism.

She explains the science in this video.