Neuropathic pain in a Fabry disease rat model. JCI Insight 2018 Mar 22;3(6)
Date
03/23/2018Pubmed ID
29563343Pubmed Central ID
PMC5926911DOI
10.1172/jci.insight.99171Scopus ID
2-s2.0-85058370681 (requires institutional sign-in at Scopus site) 42 CitationsAbstract
Fabry disease, the most common lysosomal storage disease, affects multiple organs and results in a shortened life span. This disease is caused by a deficiency of the lysosomal enzyme α-galactosidase A, which leads to glycosphingolipid accumulation in many cell types. Neuropathic pain is an early and severely debilitating symptom in patients with Fabry disease, but the cellular and molecular mechanisms that cause the pain are unknown. We generated a rat model of Fabry disease, the first nonmouse model to our knowledge. Fabry rats had substantial serum and tissue accumulation of α-galactosyl glycosphingolipids and had pronounced mechanical pain behavior. Additionally, Fabry rat dorsal root ganglia displayed global N-glycan alterations, sensory neurons were laden with inclusions, and sensory neuron somata exhibited prominent sensitization to mechanical force. We found that the cation channel transient receptor potential ankyrin 1 (TRPA1) is sensitized in Fabry rat sensory neurons and that TRPA1 antagonism reversed the behavioral mechanical sensitization. This study points toward TRPA1 as a potentially novel target to treat the pain experienced by patients with Fabry disease.
Author List
Miller JJ, Aoki K, Moehring F, Murphy CA, O'Hara CL, Tiemeyer M, Stucky CL, Dahms NMAuthors
Kazuhiro Aoki PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinNancy M. Dahms PhD Professor in the Biochemistry department at Medical College of Wisconsin
Cheryl L. Stucky PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Genetically Modified
Behavior, Animal
Disease Models, Animal
Electrophysiology
Fabry Disease
Female
Ganglia, Spinal
Gene Knockdown Techniques
Genetic Predisposition to Disease
Glycosphingolipids
Humans
Liver
Male
Neuralgia
Rats
Sensory Receptor Cells
TRPA1 Cation Channel
alpha-Galactosidase
