Dysfunction of Primary Cilium in Huntington’s Disease: How Mutant Huntingtin Disrupts This Cellular Signaling Hub, 2026, Churkina et al.

[SNT Gatchaman]

Dysfunction of Primary Cilium in Huntington’s Disease: How Mutant Huntingtin Disrupts This Cellular Signaling Hub
Churkina, Aleksandra S; Shakhov, Anton S; Alieva, Irina B

Primary cilia are solitary, antenna-like organelles that project from the surface of most vertebrate cells. They consist of a microtubule-based axoneme extending from a modified centriole (basal body) and enclosed by a lipid bilayer membrane. For several decades after their discovery, the functions of primary cilia had remained speculative; they were even considered vestigial structures. Currently, primary cilium is recognized as essential sensory and signaling structure involved in both chemo- and mechanosensation. Its anchoring at the centrosome surrounded by a radially organized network of microtubules and ability to detect extracellular signals through the axoneme protruding beyond the cell surface and enveloped by a receptor-rich membrane, make primary cilium a unique signaling hub of the cell.

The functional activity of primary cilia is critical for numerous biological processes, including embryonic development and cellular differentiation, whereas defects in ciliogenesis result in severe somatic disorders. Prominent neurological abnormalities observed in several ciliopathies have prompted investigations into the structure and function of primary cilia in other brain disorders. It has become evident that defects of neuronal primary cilia are characteristic of several monogenic neurological diseases that have not traditionally been classified as ciliopathies. A growing body of evidence indicates that many severe neurodegenerative disorders, particularly polyglutamine diseases such as Huntington’s disease, are associated with specific alterations and dysfunction of primary cilia.

In this review, we summarize current knowledge on the detrimental effects of disease-causing mutant proteins on the function of primary cilium, with particular emphasis on the disruption of PCM1 (pericentriolar material 1) trafficking by mutant huntingtin, leading to ciliary elongation and alterations in signaling pathways. We further discuss the consequences of mutant protein-induced dysfunction of this cellular antenna and analyze associated signaling pathways that may represent promising therapeutic targets. Finally, we describe potential approaches for investigating dysfunction of the neuronal signaling hub with primary cilium as an antenna.

Web | DOI | PDF | Biochemistry (Moscow) | Paywall

 

[SNT Gatchaman]

Primary cilia are immotile and, therefore, had been long regarded as vestigial structures lacking physiological function. Indeed, they had often been referred to as “abortive cilia” in early studies. This view has since been fundamentally revised. It is now well established that primary cilia function as sensory antennae that receive and integrate extracellular signals and modulate multiple signaling pathways in diverse tissues and organs.

The primary cilium, which extends from the mature centriole and projects from the cell surface, acts as a sensory antenna and represents an essential component of the signaling axis transmitting extracellular signals to the centrosome and Golgi complex, thereby ensuring efficient secretion of newly synthesized extracellular matrix components. Its membrane is enriched with a variety of specialized receptor complexes that detect and transduce extracellular signals. Importantly, the repertoire of ciliary receptors is tissue-specific. For example, the ciliary membrane of renal epithelial cells contains polycystin-2, which forms calcium-permeable channels and initiates signaling pathways regulating cell proliferation and differentiation. In these cells, the primary cilium also functions as a mechanosensor.

In neurons, primary cilia express receptors for neurotransmitters and neuropeptides, including somatostatin and serotonin, suggesting a specialized role of these structures in nervous system function.

Primary cilia act as essential cellular sensors that relay information from the extracellular environment, including nutrient availability. They transmit signals from growth factors and metabolic cues to regulate the activity of mTORC1, a protein complex that regulates autophagy, which is known to be suppressed under nutrient-rich conditions. In cultured cells, nutrient deprivation-induced growth arrest triggers both primary ciliogenesis and macroautophagy. Primary cilia are also indispensable for Sonic hedgehog (Shh) signaling and play important roles in pathways mediated by Wnt, platelet-derived growth factor, and transforming growth factor-β.

It is logical to assume that structural abnormalities of the primary cilium may affect the function of signaling pathways whose components are located in its membrane. Indeed, studies of disruptions in signaling mediated by the primary cilium or through HTT-associated proteins have shown that elongation of primary cilia induces autophagy through inhibition of mTOR signaling, while autophagy subsequently degrades proteins required for ciliogenesis. Because both autophagy and dopamine signaling are disrupted in HD, ciliary dysfunction may contribute to disease pathophysiology.

 

[Hutan]

Thanks for this SNT. Who knew that standard vertebrate cells have cilia? Not me.
So many bits in the body to go wrong, some that we probably still don't know about.

I can see that something like those primary cilia absolutely could get hit when there are infections, and nerve toxins as is likely in GWI. It sounds as though there can be long term damage, also associated with aging, but also temporary insults can cause the cilia to retract and then reappear. Could that be a PEM situation?

Regulation of the length of neuronal primary cilia and its potential effects on signalling, 2023

Primary cilia length (PCL) can substantially change within minutes to hours in response to physiological changes such as circadian rhythms and metabolic state, and secreted factors such as neurotransmitters and hormones.
The functional consequences of changes in PCL are still poorly understood, but are likely to affect cellular responses to exogenous signals across many cell types and processes.

It sounds as though if they are completely destroyed, they take much longer to be re-assembled.


But, unless the genes related to these bits are on the X chromosome, I would have thought we would have seen some genetic signal that cilia are involved in ME/CFS. I don't think we have? I do recall seeing a study or two suggesting that there were disruptions in what was labelled a Huntington Pathway, but that's a long bow, also Wnt signalling, the NOTCH pathway has been mentioned I think.

I searched for genes associated with vertebrate cilia, I couldn't see any of the ones that we talk about come up. There are some relevant genes on the X chromosome.

Some X chromosome genes relevant specifically to neuronal cilia (just noting for possible later searching)
PQBP1
OFD1
CDKL5

A more general paper on cilia on neurons:
Primary cilia in neural development and disease

This review summarizes the structural features, biogenesis, and dynamic regulation of primary cilia, and systematically examines their roles in neural stem cells fate determination, neurogenesis, neuronal migration, axon guidance, and synaptogenesis. By integrating multiple developmental signaling pathways, including Sonic hedgehog, Wnt, Notch, and mTOR, primary cilia orchestrate the precise spatiotemporal patterning of the nervous system.

Dysfunction of primary cilia is closely linked to a wide spectrum of neurodevelopmental disorders, ranging from classical ciliopathies such as Meckel–Gruber syndrome, Joubert syndrome, and Bardet–Biedl syndrome, to complex conditions such as autism spectrum disorder, schizophrenia, and bipolar disorder, all of which can be traced to ciliary signaling imbalances. This paper introduces the concept of the continuous spectrum of Ciliogenesis, in which phenotypes from severe structural malformations to subtle functional abnormalities can be attributed to defects in specific ciliary modules.

 

[SNT Gatchaman]

We should probably dig into HTT and the primary cilium a bit more. There could be a link back to sperm too. Quoting this comment from the Zhang thread —

It would be weird, and maybe is some artefact of the way they've combined the data. It's surely vanishingly unlikely sperm have anything to do with mecfs, but maybe similar sets of proteins could be used to something both neurons and sperm both need to do? Like organize the cytoskeleton to help form their cell shapes.

Or with shared building blocks, one needs to make motile cilia to swim around and the others make primary (non-motile) cilia to transduce their environment and signal between the cell and the extracellular matrix. TGF-beta gets a mention and there seems to be work on the idea that the primary cilium is directly involved in its regulation. Eg see brief overview The primary cilium at the helm: gatekeeper of TGF-β superfamily signaling in development, homeostasis, and disease (2026)

 

[SNT Gatchaman]

Another consideration with the primary cilium: one of DecodeME's tier 1 genes is RABGAP1L. From GeneCards —

RABGAP1L encodes a GTPase-activating protein that regulates protein localization and endocytic trafficking. It is a small GTPase-binding factor that localizes to the Golgi apparatus, cilium, and early endosome, placing it in membrane-trafficking compartments with distinct sorting functions.