Possible link between Proteolysis, melatonin production and Tourette's syndrome

Anecdotal reports from many people show that tics get worse during the dark hours. Our personal experience also shows clearly that disinhibition gets much worse at the bed time, often with episodes of compulsive shouting already in bed.

This prompted me to research whether this can be related to melatonin or changes that correlate with it.

Melatonin production is controlled by rapid degradation of AANAT

Melatonin is produced from serotonin by two consequential reactions: acetylation and methylation:

Through an arylalkylamine, serotonin is acetylated in N-acetylserotonin by the enzyme N-acetyltransferase and then rightly converted into melatonin by the hydroxindole-O-methyltransferase enzyme.

The N-acetyltransferase enzyme is considered the limiting factor in the synthesis of melatonin and for this reason defined as “timezyme” as its expression may have a crucial role in the modulation of the circadian rhythm (R4)

The enzyme that acetylates serotonin (AANAT) is rapidly destroyed during wake hours, and this is done by proteasomal proteolysis machinery. This proteasomal breakdown / autophagic proteolysis is the central piece of this post.

Light exposure switches off noradrenaline stimulation of pineal gland. Darkness turns on this signalling and the pineal gland starts producing melatonin.

A drug called Propranolol blocks beta-adrenergic receptors, and this blockage has the same effect on noradrenergic stimulation of pineal gland as light exposure, and it also blocks melatonin production (R1).

The study (R1) shows that this inhibiting effect of Propranolol is removed by inhibitor of proteasomal breakdown, which means that AANAT is indeed regulated by breakdown.

In other words, if we inhibit proteasomal breakdown, blocking beta-adrenergic receptors won’t have effect on melatonin production.

What is interesting now, Propranolol was shown to reduce symptoms of Tourette’s syndrome patients (R2).

That is, by inhibiting beta-adrenergic receptors by Propranolol, TS symptoms were reduced (the assumption here is that Propranolol doesn’t have other molecular effects, which is likely incorrect).

Proteolysis might be involved in TS

Let’s consider the following cascade of regulation of melatonin production:

Light exposure -> no noradrenaline -> no stimulation of beta-adrenergic receptors -> active proteolysis destroys AANAT -> no melatonin.

Darkness -> noradrenaline produced -> beta-adrenergic receptors stimulated -> proteolysis inhibited -> AANAT level and activity raises -> melatonin is produced.

My hypothesis about origins of TS suggests that

The speed of proteolysis inside the neurons is not fast enough to clear the cells from excessive amounts of p62 protein, which leads to abnormal downregulation of GABA-A receptors (R) and other metabolic dysfunctions caused by the loss of important enzymes (R).

When melatonin is produced during dark hours, the speed of protein breakdown is even lower to support melatonin synthesis and therefore the rate of ubiquitination should be higher than during the day.

At the same time, Nrf2 activation by melatonin leads to additional synthesis of the p62 protein, because p62 is a direct target of Nrf2.

This suggested connection between reduced proteolysis and lowered GABAergic signalling is supported by the study R3 that shows that chronic treatment with Propranolol increases GABAergic function:

Prolonged administration of propranolol increased GABA content, synthesis and turnover rate in the hypothalamus and the pons-medulla. … Our results indicate that propranolol increases GABAergic system activity. Therefore, we conclude that down-regulation of the GABAergic system in hypertension may be compensated by the regulatory action of propranolol. (R3)

DHA inhibits proteolysis

I shared a note in January 2024 that DHA (Omega-3) appears to inhibit proteolysis by increasing oxidative stress: DHA inhibits proteolysis.

This can explain why tics and mental issue become much worse in some people after taking Omega-3.

Concluding remarks

I’m not suggesting you to start taking Propranolol, but you can discuss this hypothesis with your doctor. Based on my understanding, stimulating proteolysis COULD be beneficial in general and for TS patients especially.

My current goal is to figure out why the rate of proteolysis is not sufficient and to figure out what comes first: reduced proteolysis (impaired autophagy) or increased ubiquitination/increased p62 due to chronic Nrf2 activation.