Ryanodine channel disfunction also causes essential tremor.

Essential tremor is the most common type of tremor characterized by an 8 Hz kinetic tremor (shaking whenever the patient tries to move), and it appears have a very diverse set of causes that all converge on the same symptom, tremor.

Essential tremor is caused by pathological synchronization of the cerebellum, that is the sole output neuron of the cerebellum, the Purkinje cells are all firing in lock-step with each other. That is why disrupting cerebellar output using deep brain stimulation on the cerebellar projection's route through the thalamus so effective at treating tremor. However, there are potentially many different causes of pathological synchronization of the cerebellum. Ranging from up-regulation of ion channels in the inferior olive, to overgrowth of climbing fibers in the Purkinje cell layer.

Today however, we are going to talk about a third potential mechanism that can cause pathological synchronization of the cerebellum, and thus cause essential tremor. Recently a paper by Dr. Regina Martuscello and her team, released a paper showing that post-transnational changes of ryanodine channels is found in patients with essential tremor. When a mutation of the ryanodine channel is given to mice, the mice develop essential tremor.

In order to explain how this works, we first must review some basic cell biology. Cells tightly regulate the amount of calcium present in the cytosol. They usually keep the concentration at about 2 nM, which is very very low compared to the extracellular concentration of 2 mM. This million-fold difference in calcium means that any calcium influx into the cell will signal the cell to perform actions. This can be anything from up regulating neurotransmitter receptors, committing to muscle contractions, all the way up to initiating cell death.

As such it is very important to keep calcium concentration low and spatially segregated within a cell, especially neurons. To help with this cells have an endoplasmic reticulum(ER), that among many different functions also stores calcium. Sometimes, the cell wants to have a control release of these stores to signal some action for the cell to perform. In order to do that, the ER has many different calcium channels on the ER that let calcium out of the ER stores.

One of those channels is the ryanodine channels. Ryanodine is a calcium activated calcium channel that is found on the surface of the endoplasmic reticulum. That means ryanodine opens up when cytosolic calcium is elevated causing a cascade of calcium release in the presence of elevated calcium.

Inside Purkinje cells the ryanodine channels should be closed when calcium levels are low. However, for currently unknown reasons ryanodine channel has a bunch of pathological post-transnational changes applied to it. There are excessive phosphorylations, oxidations, and nitrosylations applied to the channel. Moreover, calstabin1, a protein that stabilizes the channel, is depleted. These changes are characteristic of a leaky ryanodine channel, or a ryanodine channel that cannot close.

Examples of a leaky channel. Little blobs of ER membranes called microsomes are put into a bath with calcium and florescent indicator. The microsomes are embedded with ryanodine channels. ATP is used get the microsomes to pump calcium into the microsomes. Thapsigargin reduces calcium pump activity. As a result, the leakiness of essential tremor (ET) ryanodine channels becomes apparent, as they leak much more calcium back into the bath than the control. Rycal ARM210 is a drug that restabilizes the ryanodine channel much like calstabin1.

However, just because a deficiency  is found in a human population doesn't mean its causal. Luckily for Dr. Martuscello's, a genetic mutation RyR1-S2844D has the same leaky ryanodine channel profile as the ET pateints. When mice are bred with the RyR1-S2844D mutation, they too develop the tremor. This means, at least for some subset of the population, that ryanodine channel leakiness is a prime suspect for causing ET.

This is a very new study, so its not quite known how elevated cytosolic calcium concentrations cause tremor. Purkinje cells are know for having dendritic calcium spikes during normal function, as well as having a wealth of calcium channels and calcium activated potassium channels. Perhaps there is some feedback loop between the surface membrane and the ER creating pathological oscillations in the Purkinje cells. It is too soon to tell, but there will certainly be a lot of follow up work to figure out how exactly leaky ryanodine receptors cause synchronization of the cerebellum and ultimately cause essential tremor.

Author: Alex White

Source: Martuscello RT, Chen ML, Reiken S, Sittenfeld LR, Ruff DS, Ni CL, Lin CC, Pan MK, Louis ED, Marks AR, Kuo SH. Defective cerebellar ryanodine receptor type 1 and endoplasmic reticulum calcium ‘leak’in tremor pathophysiology. Acta Neuropathologica. 2023 Jun 19:1-8.