Edit in response to feedback in comments requesting specific details, etc.: Will aqueously diffusible protein oligomers and protofibrils coated in cell-free nucleic acids in the aqueous interstitial space near the neural soma of a cluster of long-projecting hippocampal pyramidal neurons diffuse along the length of their axons (i.e., parallel to the velocity of the axon potential) if the neurons depolarize, causing them to migrate from near the cluster of hippocampal pyramidal neurons proximal to the group of neurons their axons are synapsing with in a neocortical association cortex as part of the default-mode network?
To clarify a commment, we already have evidence (most of it already published) that these aqueously soluble and diffusible nucleic acid-coated protein oligomers and protofibrils do accumulate significantly in the cerebral cortices (and probably the hippocampi and entorhinal cortices too) of patients with the disorder we study compared to those of control individuals who passed away without this disorder. However, we do not know if these particles diffuse stochastically with no net vector, or whether they might migrate in specific directions under some circumstances, which could promote inter-regional seeding of these aggregates. This is not something we intend to build.
I think nucleic acids (and proteins) diffuse in a partially charge-density dependent manner through aqueous spaces in a voltage gradient. For example, Bass and Weintraub found that RNA duplexes migrated further than their constituent RNA monomers did on native 4% polyacrylamide gel electrophoresis (PAGE) (1). RNA duplexes have a higher mass than monomers, but they have approximately twice as much charge density. As they wrote, "RNA was extracted from these oocytes and embryos and analyzed by electrophoresis in a native 4% polyacrylamide gel. This gel system easily resolves the faster migrating duplex RNA (D) resulting from the hydridization of sense and antisense CAT RNA from nonhybridized monomer RNA (M) (Figure 1)." Below is their Figure 1 (A) showing the gel in question, with the legend stating it is a native gel.
As far as I understand it, native (i.e., non-denaturing) PAGE is a somewhat ideal model of the aqueous diffusion of small charged particles. Polyacrylamide mixed with water forms a gel with small holes in it. Molecules are free to diffuse in the aqueous phase, but they have to pass through these holes to migrate far. Negatively charged particles are pulled towards the positively charged electrode (anode). SDS-PAGE is a common variant of PAGE wherein proteins migrate according to their size, because they're denatured and coated evenly with the negatively charged chaotrope SDS, making their charge roughly proportional to their size.
Here is a GIF of a depolarizing neuron to help visualize the question:
As a simplifying assumption, let's say it's improbable that the nucleic acid-coated protein aggregates will cross the plasma membrane. In reality, oligomers of this particular protein, and structurally and functionally analogous virus-like particles, can cross the plasma membrane primarily via heparan sulfate proteoglycan-mediated macropinocytosis, and secondarily via clathrin-mediated endocytosis. Whereas, soluble fibrils of this particularly protein do not get taken up by cells (at least the larger fibrils). I would rather not provide citations to these claims, as it's not necessary to understand or answer the question, and doing so would give away what I'm working on specifically, which I would rather not do publicly yet.
- Bass, B. L. & Weintraub, H. A developmentally regulated activity that unwinds RNA duplexes. Cell 48, 607–613 (1987).
Original post: Let's say there's a small, densely negatively charged object just outside the cell body of a neuron. It is freely diffusible in the aqueous interstitial space. Let's say it's improbable that it will cross the plasma membrane to enter the neuron. Then the neuron depolarizes. Is enough of a voltage gradient (and electromagnetic field) created by deplarization that it will cause the negatively charged object to diffuse? If so, in what direction? Will it diffuse down the length of the neural axon as it depolarizes?
What if the object can cross the plasma membrane? Then will it likely do so?
This object diffuses far in a native polyacrylamide gel electrophoresis (PAGE).
