Genetics: CCPG1

[Hutan]

DecodeMe Candidate Gene

In DecodeME, we attempted to link GWAS variants to target genes. Here we discuss the top two tiers of predicted linked genes that we are most confident about –‘Tier 1’ and ’Tier 2’.

We defined genes as Tier 1 genes if: (i) they are protein-coding genes, (ii) they have GTEx-v10 expression quantitative trait loci (eQTLs) lying within one of the FUMA-defined ME/CFS-associated intervals, and (iii) their expression and ME/CFS risk are predicted to share a single causal variant with a posterior probability for colocalisation (H4) of at least 75%. For this definition, we disregarded the histone genes in the chr6p22.2 HIST1 cluster, as their sequences and functions are highly redundant (1). This prioritisation step yielded 29 Tier 1 genes.

For the intervals without Tier 1 genes, three Tier 2 genes were defined as the closest protein-coding genes without eQTL association: FBXL4 (chr6q16.1), OLFM4 (chr13q14.3), and CCPG1 (chr15q21.3).

CHROMOSOME 15
Chr15 contained no Tier 1 genes and one Tier 2 gene.

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CCPG1 (Tier 2)

• Protein: Cell cycle progression 1. UniProt. GeneCards.

• Molecular function: Involved in positive regulation of cell cycle and positive regulation of cell population proliferation. Type II single-pass transmembrane protein. Acts as an assembly platform for Rho protein signalling complexes. Limits guanine nucleotide exchange activity of MCF2L toward RHOA. CCPG1 is a reticulophagy (ER-phagy) receptor. It binds GABARAP (an ATG8-family member) which also binds the gamma-2 subunit of the GABAA receptor, and promotes trafficking of these receptors and their clustering at synapses.

• Cellular function: CCPG1 is an ER-resident protein that acts as an ER stress- and/or unfolded protein response-inducible ER-phagy cargo receptor. It facilitates ER-phagy, via binding to core autophagy proteins, ATG8 and FIP200. CCPG1 protects against ER luminal protein aggregation and consequent unfolded protein response hyperactivation and tissue injury of the exocrine pancreas (57).

• Link to disease: Other autophagy genes, but not CCPG1, are proposed to be mutated in human disease (58). ER-phagy is a host defense mechanism when pathogens infect cells, and its deficiency facilitates viral infection (59).

• Potential relevance to ME/CFS: Potentially in host resistance to infection and/or as an anti-inflammatory factor. ATG13 recruits ULK1, RB1CC1, and ATG101 to the ULK1 complex, essential for initiating and then regulating autophagy. ATG8 is conjugated to the phosphatidylethanolamine (PE) lipid, which then becomes incorporated into the autophagosomal membrane. CCPG1 interacts with all ULK1 complex members in A549 cells (57). ATG13 was strongly upregulated in a study of serum samples of ME/CFS patients (60). Autophagy is inherently anti-inflammatory, as its effects are to remove microbes, damaged organelles, or protein aggregates that otherwise evoke inflammatory signals (61).

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References

57 Smith MD, Harley ME, Kemp AJ, Wills J, Lee M, Arends M, et al. CCPG1 Is a Non-canonical Autophagy Cargo Receptor Essential for ER-Phagy and Pancreatic ER Proteostasis. Dev Cell. 2018 Jan 22;44(2):217-232.e11.

58 Yamamoto H, Zhang S, Mizushima N. Autophagy genes in biology and disease. Nat Rev Genet.2023 Jun;24(6):382–400.

59 Li J, Gao E, Xu C, Wang H, Wei Y. ER-Phagy and Microbial Infection. Front Cell Dev Biol. 2021;9:771353.

60 Gottschalk G, Peterson D, Knox K, Maynard M, Whelan RJ, Roy A. Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE). Mol Cell Neurosci. 2022 May;120:103731.
Forum thread

61 Deretic V. Autophagy in inflammation, infection, and immunometabolism. Immunity. 2021Mar 9;54(3):437–53.

 

[Hutan]

See also

Thread 'Inactivation of ATG13 stimulates chronic demyelinating pathologies in muscle‑serving nerves and spinal cord, 2025, Drosen et al.'

Jan 7, 2025

Abstract
Chronic muscle fatigue is a condition characterized by debilitating muscle weakness and pain. Based on our recent finding to study the potential effect of mTOR on ATG13 inactivation in chronic muscle fatigue, we report that biweekly oral administration with MHY1485, a potent inducer of mTOR, develops chronic illness in mice resulting in severe muscle weakness. As a mechanism, we observed that MHY1485 feeding impaired ATG13-dependent autophagy, caused the infiltration of inflammatory M1 macrophages (Mφ), upregulated IL6 and RANTES by STAT3 activation, and augmented...

• InitialConditions
• atg13 avik roy fatigability gottschalk muscle fatigability
• Replies: 25
• Forum: ME/CFS research

• 

although note that that paper relates to inactivation of ATG13 and it's unclear how that relates to increased serum levels of ATG13.

 

[Jonathan Edwards]

My guess is that cell cycle is a red herring - most of the information is about autophagy and innate clearance mechanisms anyway. Again, my guess is that this is a gene involved in housekeeping cell junk handling.

I am getting this picture of supervisor hypothalamic microglia nagging the neurons about what a terrible state all the properties the cleaning staff visit out there in the body are in and producing debris to prove it, when if you look at the supervisor's office it is just as bad and for the same underlying reason.

That may be complete nonsense of course but I am trying to account for all these genes somehow!

 

[Jonathan Edwards]

Note that anti-inflammatory creeps in. Jo Cambridge keeps telling me ME/CFS is anti-inflammatory.

 

[V.R.T.]

Note that anti-inflammatory creeps in. Jo Cambridge keeps telling me ME/CFS is anti-inflammatory.

Could you possibly expand on this a little? You've mentioned this idea before but I can't get my head around it.

 

[Jonathan Edwards]

Could you possibly expand on this a little? You've mentioned this idea before but I can't get my head around it.

We can't get our heads around it either much. Suggestions of TGF beta being up is one thing. And the immune system seems to be busy but without any inflammation to see. Other things in Jo's CD24 story fit with this but I forget the detail.

 

[Kitty]

Note that anti-inflammatory creeps in. Jo Cambridge keeps telling me ME/CFS is anti-inflammatory.

And the immune system seems to be busy but without any inflammation to see.

As in, it'd be normal to see inflammation markers rising and falling according to various factors, and there's less of it in ME/CFS?

I wondered if it could mean a boot was coming down heavily on processes that don't warrant a strong response, or an ongoing one. Probably not, though.

 

[Jonathan Edwards]

As in, it'd be normal to see inflammation markers rising and falling according to various factors, and there's less of it in ME/CFS?

Not so much that. People with ME/CFS have ordinary amounts of inflammation when appropriate as far as I know. But the illness itself seems to involve signals that put the immune system on 'yellow alert' and stop people going for a paddle in the sea.

 

[Utsikt]

I am getting this picture of supervisor hypothalamic microglia nagging the neurons about what a terrible state all the properties the cleaning staff visit out there in the body are in and producing debris to prove it, when if you look at the supervisor's office it is just as bad and for the same underlying reason.

Are the supervisors able to initiate interventions if they think it’s necessary? So it’s kind of an issue with the tuning of the decision making process of the supervisors?

And what about the debris from the rest of the body, is that supposed to be there or is it being brought in through some kind of faulty process?

 

[Jonathan Edwards]

Excellent questions. The metaphor may not go quite that far but who knows?

 

[hotblack]

I think I see what you mean. Learning about these genes there seems to be a lot about what is let into or out of cells, cleanup and communication between them (particularly neurons).

So in a complex and busy environment having your doormen and your maintenance crews behave just a little ‘off’ or just differently (to another person’s), may not be a problem normally, but in an emergency situation could be the difference between things being fine or triggering/contributing towards something going wrong?

Perhaps cascading or getting caught in a feedback loop such as you’ve proposed before?

There could be other mechanisms. There could be a rarer gene or genes we could find in a full genome study which would show us these. Or we may be able to find or at least guess at them with what we’ve got.

Last night I was thinking about inefficient or faulty garbage collection, in cells in terms of waste or byproducts from activity or infection, but also in terms of another computer science reference and the impacts there (often not good).

 

[hotblack]

More analogy and speculation, so maybe better elsewhere but since I’ve started…

I’ve been thinking more about some of these ideas and about concepts in computer science and how I’ve seen things go wrong. A little primer

Reference counting garbage collection is where each object has a count of the number of references to it. Garbage is identified by having a reference count of zero. An object's reference count is incremented when a reference to it is created and decremented when a reference is destroyed. When the count reaches zero, the object's memory is reclaimed

https://en.m.wikipedia.org/wiki/Garbage_collection_(computer_science)
https://en.m.wikipedia.org/wiki/Reference_counting

So let’s imagine the brain does something similar for activity rather than memory (which I guess would be an easier analogy). It’s useful for the brain to know how active we have been. To stop us running at full tilt all the time or stop before harming ourselves. Maybe it doesn’t just depend upon feedback mechanisms of lactic acid build up or whatever but tracks say, neurons firing.

I’m envisioning a system where the brain tracks things in a similar way to reference counting. But in this case it does so by forming neuronal connections. It stores references or a tally of these so it knows when a threshold of connections has been reached or is near being reached. And normally it frees or cleans them up over time.

Maybe the brain uses the same mechanism to tell the body to do less when ill, so if immune signals are being sent this also increments the counter in the same way other neurological signals do.

Now what if something is going wrong here. Either something is incrementing the counter more than it should or not freeing the references when it should, or perhaps both? Maybe the connections are formed more easily or it’s harder to break them. Either way we end up over the thresholds more easily and more of the time. The brain thinks we’ve exceeded a threshold it’s trying to track, so responds accordingly.

A bunch of these genes sort of seem to be implicated in areas I can see being involved here. And some of this sort of fits with some stuff I’ve read about neuroscience. But is very woolly I know.

 

[Jonathan Edwards]

A bunch of these genes sort of seem to be implicated in areas I can see being involved here. And some of this sort of fits with some stuff I’ve read about neuroscience. But is very woolly I know.

I agree. And it is going to be woolly because this is uncharted territory. But ME/CFS has always looked to be in uncharted territory!

 

[jnmaciuch]

I’m envisioning a system where the brain tracks things in a similar way to reference counting. But in this case it does so by forming neuronal connections. It stores references or a tally of these so it knows when a threshold of connections has been reached or is near being reached. And normally it frees or cleans them up over time.

It's an interesting idea! Though the few studies we have looking at neural "tracking" of cumulative activity point to a more simplistic metabolic explanation--both in peripheral sensing of metabolites from muscle and accumulation of metabolic byproducts in the brain that double as neurotransmitters (meaning that the very byproducts of neurons being metabolically active inhibit further neural activity). If those findings are right, there would still be a garbage collection process, just a fairly literal one.

 

[hotblack]

Though the few studies we have looking at neural "tracking" of cumulative activity point to a more simplistic metabolic explanation

Interesting thanks for the insight @jnmaciuch What do you think about it being more or a metabolic issue which then impacts the finely balanced immune and nervous systems? So these genes pop up because (as a population) we have some things a bit different, which normally isn’t an issue, but if metabolism goes wrong, these ‘cracks’ are exposed as it were?

 

[hotblack]

I agree. And it is going to be woolly because this is uncharted territory. But ME/CFS has always looked to be in uncharted territory!

Hopefully our novelty now gets people (including some neuroscientists) involved!

It was also a bit more than just activity I was thinking. A lot of our symptoms do seem to be about normal signals, some have described them as over-reactivity or oversensitivity or other similar words. But what if it’s just that these signals are not turned off or cleaned up or not accounted for properly. So any temporary connections between neurons persist longer than they should, are not returned to defaults after 24 hours. So we have this cumulative effect which we can also never fully get back to normal.

The brain thinks here has been more noise, more light, more activity or whatever input than there has. So responds to that (causing the other symptoms). It’s a different way of these thresholds being changed. But the idea of threshold and action potentials got me interested when reading about them and multiple axons/dendrite working in such a complex way to fire a single neuron. And when some of the functions of these genes all pop up, it all also seems very synapse related. Maybe it’s something more direct which changes those thresholds at the cell membrane though.

 

[Jonathan Edwards]

The brain thinks here has been more noise, more light, more activity or whatever input than there has. So responds to that (causing the other symptoms). It’s a different way of these thresholds being changed.

Yes, that sort of explanation, unlike the predictive coding story the FND people tell, could make sense. (For ME/CFS, I still fail to see how it would explain the involuntary movements of FND.)

 

[jnmaciuch]

Interesting thanks for the insight @jnmaciuch What do you think about it being more or a metabolic issue which then impacts the finely balanced immune and nervous systems? So these genes pop up because (as a population) we have some things a bit different, which normally isn’t an issue, but if metabolism goes wrong, these ‘cracks’ are exposed as it were?

That’s a possibility!

 

[chillier]

Noting a potential commonality between CCPG1 and ARFGEF2 in the trafficking of GABA receptors.

 

[chillier]

There is a lab working on CCPG1 in the context of autophagy apparently in the same building as Chris Ponting's lab:

Simon Wilkinson: Autophagy in Tissue Homeostasis and Cancer | Institute of Genetics and Cancer | Institute of Genetics and Cancer

Research Programme

institute-genetics-cancer.ed.ac.uk

"We are also interested in the mechanisms by which autophagy ‘remodels’ cells during metaplasia. Metaplasia involves the conversion of one cell type to another, sometimes via generation of a proliferative, stem-like intermediate. This occurs during both tissue renewal and tumourigenesis in certain organs, such as the exocrine pancreas (where acinar cells provide either facultative stem cells for tissue regeneration, or seeds for cancer). We have discovered that, in the absence of a new gene (Ccpg1) that we recently showed to drive ER-phagy (selective degradation of the endoplasmic reticulum by autophagy), oncogene-driven metaplasia is associated with increased inflammation and desmoplasia, driving tumorigenesis. We are dissecting this phenomenon mechanistically and are screening for therapeutic agents to modify it."