Fabry Disease: Ion channels and neuropathic pain
Pain behaviors in a Fabry mouse model are associated with the accumulation of a fat molecule that disrupts sodium ion channels in small fiber neurons.
- Massachusetts General Hospital, United States
- Harvard University, United States
In our bodies, peripheral nerve cells of different thicknesses connect the brain to the outside world. Most of these neurons are unidirectional. They either send information to our brain about what takes place in or around the body, or they respond and then relay signals outward from the brain to the muscles and other cells. However, least-evolved neurons called C-fibers still work in ancient and undisciplined ways, and do not always obey the rules of neuroanatomy. For instance, they are bidirectional: in addition to encoding and transmitting messages inward to the spinal cord and the brain when they encounter dangerous stimuli, these small diameter neurons also convey signals outward to a wide range of nearby cells throughout the body (Fukuda et al., 2013; Dori et al., 2015).
It is no wonder, then, that peripheral neuropathies which damage small fibers lead to a bewildering array of symptoms: chronic widespread pain that often starts in the feet and legs, dizziness, weakness with exertion (also known as chronic fatigue), fainting upon standing, nausea, constipation or diarrhea, and itching (Terkelsen et al., 2017). With such nonspecific symptoms, it is often difficult to diagnose the neuropathy and then its underlying medical cause. Although neuropathy often appears because of diabetes or toxic exposures, in very rare cases it can emerge because of genetic mutations. Studying these exceptional patients is a time-honored way of figuring out the mechanisms that lead to these symptoms.
One such example is Fabry disease, a rare inherited disorder caused by mutations on the X-chromosome, meaning it affects males more often and more seriously than females. Children with the condition often begin to notice episodes of burning pain, less sweating in their feet and hands, and digestive difficulties. This pain can flare up when their temperature rises as a result of exercise, fever or hot weather. The mutation responsible for Fabry disease targets an enzyme called α-22 galactosidase A (α-GAL), an enzyme that breaks down and helps recycle a fat molecule known as Gb3 (short for globotriaosylceramide). When the enzyme is not fully functional, Gb3 is not degraded and instead accumulates inside the cell.
The α-GAL enzyme is expressed in small fiber neurons and the lining of blood vessels. Because small fibers also partly regulate many blood vessels, dysfunctional α-GAL is a double blow to the circulatory system. Indeed, when patients get older, many develop vascular problems such as strokes, and heart and kidney damage (Gupta et al., 2005). As treatments that aimed to replace α-GAL were developed, some countries and states began to screen newborns for Fabry (Hopkin et al., 2016). However, researchers did not fully understand how the accumulation of undigested Gb3 caused small fiber neurons to fail.
Now, in eLife, Nurcan Üçeyler of the University of Würzburg and co-workers at Würzburg and Yale Medical School and Veterans Affairs Hospital – including Lukas Hofmann as first author – fill in some of the blanks (Hofmann et al., 2018). The team elegantly combined molecular, histological, electrophysiological and behavioral techniques to study a mouse model of Fabry disease in which the gene for α-GAL has been deactivated (or ‘knocked out’). It was already known that as these mice get older, Gb3 accumulates within and around the cell bodies of their small fiber neurons in the sensory ganglia (Gadoth and Sandbank, 1983; Hofmann et al., 2018). Located near the spinal cord, these ganglia help the body process sensations.
Hofmann et al. went on to examine how the α-GAL knockout mice respond to pain – for example, how long it takes them to withdraw a hind paw from a hot surface. When comparing young and old animals with or without the mutation, the team showed that older mice with the genetic change developed abnormal pain responses. In these animals, the farthest ends of the small fiber neurons had degenerated, which is the pathological hallmark of small fiber neuropathy.
The team then focused on three specific ion channels that are important to small fiber function, recording their activity using a method known as patch clamp. Ion channels are proteins which span the cellular membrane and open or close in response to the local environment. This allows ions to pass into and out of the cell to create an electrical signal that can travel along the neuron, making it ‘fire’. In older mice, the function of two of these ion channels, HCN2 and the sodium channel NaV1.7, had deteriorated as compared to normal controls. Not surprisingly, both channels had already been linked to small fiber neuropathic pain (Emery et al., 2011; Faber et al., 2012).
Then, as a coup de grace, Hofmann et al. used RNA interference to silence α-GAL in a culture of embryonic kidney cells that expressed NaV1.7 channels on their membranes. This caused Gb3 to accumulate in these cells, and their sodium currents to falter. When the cells were then exposed to an existing treatment for Fabry disease, which restores α-GAL, healthy NaV1.7 currents were reestablished and the Gb3 deposits decreased.
Although the work by Hofmann et al. does not explain how the accumulation of Gb3 affects Nav1.7 channels, or clarify if other ion channels are involved, it does demonstrate that increased amounts of Gb3 can lead to pathologic, physiologic, and behavioral signs of neuropathy. Armed with this knowledge, researchers might be able to develop new, non-genetic ways to reduce Gb3 deposition. This could be valuable to Fabry patients, as the current α-GAL replacement treatment is prohibitively expensive and does not always ensure that Gb3 is broken down around the clock. The cell lines and methods developed by Hofmann et al. could also help researchers study other disorders where waste products are not properly recycled and to identify other, more common, causes of small fiber neuropathy.
References
-
Myovascular innervation: Axon loss in small-fiber neuropathiesMuscle & Nerve 51:514–521.https://doi.org/10.1002/mus.24356
-
Gain of function Nav1.7 mutations in idiopathic small fiber neuropathyAnnals of Neurology 71:26–39.https://doi.org/10.1002/ana.22485
-
Involvement of dorsal root ganglia in Fabry's diseaseJournal of Medical Genetics 20:309–312.https://doi.org/10.1136/jmg.20.4.309
-
The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease: a cross-sectional study of a large cohort of clinically affected heterozygous womenMedicine 84:261–268.
-
The management and treatment of children with Fabry disease: A United States-based perspectiveMolecular Genetics and Metabolism 117:104–113.https://doi.org/10.1016/j.ymgme.2015.10.007
Article and author information
Author details
Anne Louise Oaklander
Publication history
Copyright
© 2018, Klein and Oaklander
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,567
- views
-
- 178
- downloads
-
- 8
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Fabry Disease: Ion channels and neuropathic pain
eLife 7:e42849.
https://doi.org/10.7554/eLife.42849
Further reading
-
- Neuroscience
Perceptual systems heavily rely on prior knowledge and predictions to make sense of the environment. Predictions can originate from multiple sources of information, including contextual short-term priors, based on isolated temporal situations, and context-independent long-term priors, arising from extended exposure to statistical regularities. While the effects of short-term predictions on auditory perception have been well-documented, how long-term predictions shape early auditory processing is poorly understood. To address this, we recorded magnetoencephalography data from native speakers of two languages with different word orders (Spanish: functor-initial vs Basque: functor-final) listening to simple sequences of binary sounds alternating in duration with occasional omissions. We hypothesized that, together with contextual transition probabilities, the auditory system uses the characteristic prosodic cues (duration) associated with the native language’s word order as an internal model to generate long-term predictions about incoming non-linguistic sounds. Consistent with our hypothesis, we found that the amplitude of the mismatch negativity elicited by sound omissions varied orthogonally depending on the speaker’s linguistic background and was most pronounced in the left auditory cortex. Importantly, listening to binary sounds alternating in pitch instead of duration did not yield group differences, confirming that the above results were driven by the hypothesized long-term ‘duration’ prior. These findings show that experience with a given language can shape a fundamental aspect of human perception – the neural processing of rhythmic sounds – and provides direct evidence for a long-term predictive coding system in the auditory cortex that uses auditory schemes learned over a lifetime to process incoming sound sequences.
-
- Cell Biology
- Neuroscience
Reactive astrocytes play critical roles in the occurrence of various neurological diseases such as multiple sclerosis. Activation of astrocytes is often accompanied by a glycolysis-dominant metabolic switch. However, the role and molecular mechanism of metabolic reprogramming in activation of astrocytes have not been clarified. Here, we found that PKM2, a rate-limiting enzyme of glycolysis, displayed nuclear translocation in astrocytes of EAE (experimental autoimmune encephalomyelitis) mice, an animal model of multiple sclerosis. Prevention of PKM2 nuclear import by DASA-58 significantly reduced the activation of mice primary astrocytes, which was observed by decreased proliferation, glycolysis and secretion of inflammatory cytokines. Most importantly, we identified the ubiquitination-mediated regulation of PKM2 nuclear import by ubiquitin ligase TRIM21. TRIM21 interacted with PKM2, promoted its nuclear translocation and stimulated its nuclear activity to phosphorylate STAT3, NF-κB and interact with c-myc. Further single-cell RNA sequencing and immunofluorescence staining demonstrated that TRIM21 expression was upregulated in astrocytes of EAE. TRIM21 overexpressing in mice primary astrocytes enhanced PKM2-dependent glycolysis and proliferation, which could be reversed by DASA-58. Moreover, intracerebroventricular injection of a lentiviral vector to knockdown TRIM21 in astrocytes or intraperitoneal injection of TEPP-46, which inhibit the nuclear translocation of PKM2, effectively decreased disease severity, CNS inflammation and demyelination in EAE. Collectively, our study provides novel insights into the pathological function of nuclear glycolytic enzyme PKM2 and ubiquitination-mediated regulatory mechanism that are involved in astrocyte activation. Targeting this axis may be a potential therapeutic strategy for the treatment of astrocyte-involved neurological disease.
