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.
-
Download
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 paineLife 7:e42849.https://doi.org/10.7554/eLife.42849 - Cite
- CommentOpen annotations (there are currently 0 annotations on this page).
- 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
-
- 8
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Further reading
-
- Neuroscience
Detecting causal relations structures our perception of events in the world. Here, we determined for visual interactions whether generalized (i.e. feature-invariant) or specialized (i.e. feature-selective) visual routines underlie the perception of causality. To this end, we applied a visual adaptation protocol to assess the adaptability of specific features in classical launching events of simple geometric shapes. We asked observers to report whether they observed a launch or a pass in ambiguous test events (i.e. the overlap between two discs varied from trial to trial). After prolonged exposure to causal launch events (the adaptor) defined by a particular set of features (i.e. a particular motion direction, motion speed, or feature conjunction), observers were less likely to see causal launches in subsequent ambiguous test events than before adaptation. Crucially, adaptation was contingent on the causal impression in launches as demonstrated by a lack of adaptation in non-causal control events. We assessed whether this negative aftereffect transfers to test events with a new set of feature values that were not presented during adaptation. Processing in specialized (as opposed to generalized) visual routines predicts that the transfer of visual adaptation depends on the feature similarity of the adaptor and the test event. We show that the negative aftereffects do not transfer to unadapted launch directions but do transfer to launch events of different speeds. Finally, we used colored discs to assign distinct feature-based identities to the launching and the launched stimulus. We found that the adaptation transferred across colors if the test event had the same motion direction as the adaptor. In summary, visual adaptation allowed us to carve out a visual feature space underlying the perception of causality and revealed specialized visual routines that are tuned to a launch’s motion direction.
-
- Neuroscience
The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence of nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to the emergence of motor issues, patients frequently experience non-motor symptoms, such as a reduced sense of smell (hyposmia). The cellular and molecular bases for these early defects remain enigmatic. To explore this, we developed a new collection of five fruit fly models of familial Parkinsonism and conducted single-cell RNA sequencing on young brains of these models. Interestingly, cholinergic projection neurons are the most vulnerable cells, and genes associated with presynaptic function are the most deregulated. Additional single nucleus sequencing of three specific brain regions of Parkinson’s disease patients confirms these findings. Indeed, the disturbances lead to early synaptic dysfunction, notably affecting cholinergic olfactory projection neurons crucial for olfactory function in flies. Correcting these defects specifically in olfactory cholinergic interneurons in flies or inducing cholinergic signaling in Parkinson mutant human induced dopaminergic neurons in vitro using nicotine, both rescue age-dependent dopaminergic neuron decline. Hence, our research uncovers that one of the earliest indicators of disease in five different models of familial Parkinsonism is synaptic dysfunction in higher-order cholinergic projection neurons and this contributes to the development of hyposmia. Furthermore, the shared pathways of synaptic failure in these cholinergic neurons ultimately contribute to dopaminergic dysfunction later in life.
