Post by Sarah Hill
What's the science?
The proteins expressed in a cell drive its biological function. Neurons express ~12,000 different proteins that facilitate a number of functions, including rapid neurotransmission. Proteins are translated from a template mRNA, (protein synthesis), assuming that this occurs as a constant, steady-state process within the neuronal soma (cell body). However, unlike other round cells, neurons have a complex morphology with dendrites and axons branching out from the cell body forming synapses with other neurons. Proteins are required to enable functions such as neurotransmission at synaptic sites located a great distance from the cell body, on short notice. Previous research has demonstrated that a large fraction of postsynaptic (dendritic) proteins are translated locally within dendrites, offering an alternative mechanism to proteins being shuttled from the cell body to the dendrite where they are expressed. This week in Neuron, Fonkeu and colleagues offer new mechanistic insights on mRNA and protein turnover and propose a mathematical model that reliably incorporates the temporal and spatial dynamics of neuronal protein synthesis.
How did they do it?
To model the complex distribution of mRNA within a neuron, the authors first derived an equation that describes the production of an mRNA transcript in the cell nucleus, its subsequent transport to the soma and dendrites, and eventually, its degradation. They then derived a similar formula for neuronal protein distribution, based on a protein's translation from mRNA in the soma or dendrites, its potential transport throughout the cell, as well as its deterioration, noting that the protein distribution model eventually converges such that mRNA and protein synthesis, transport, and degradation balance out. To validate the model, the mRNA and protein formulas were applied using data for CaMKIIα, a key postsynaptic protein, important for synaptic plasticity. The CaMKIIα distribution predicted by the theoretical model was then compared to the distribution obtained experimentally through in situ hybridization and immunohistochemistry.
What did they find?
Derivation of protein and mRNA distribution formulas enabled the authors to mathematically differentiate between distributions of proteins generated from somatic mRNA and those generated from dendritic mRNA. The distribution obtained experimentally closely matched that predicted by the model; the model indicated that 60% of CaMKIIα proteins were synthesized in dendrites. The model also successfully described three alternative protein distribution patterns, demonstrating its utility for a wide variety of protein and mRNA targets. Finally, they demonstrated the model's value in exposing how various formula parameters, such as mRNA transport velocity, diffusion coefficient, and degradation rate, affect final protein distribution. A slight decrease in mRNA transport velocity, for example, significantly alters the distribution outcome, while a mild to moderate change in the diffusion coefficient does not.
What's the impact?
This is the first study to propose a model outlining the role of mRNA localization and dendritic translation of mRNA into protein far from the cell body in synaptic function. Given the high rates of mRNA and protein turnover, as well as the potential for mRNA localization in either somatic or dendritic sites, an overhaul of existing methods for predicting the distribution of proteins is needed to better capture the highly dynamic processes of neuronal transcription and translation. The model proposed in this study offers an improvement by better encompassing the range of biological nuances that regulate neuronal mRNA and protein stores.
Fonkeu et al. How mRNA Localization and Protein Synthesis Sites Influence Dendritic Protein Distribution and Dynamics. Neuron (2019).Access the original scientific publication here.