Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease
Giant axonal neuropathy (GAN) is an inherited severe sensorimotor neuropathy. The aim of this research was to investigate the neuropathologic features and clinical autonomic nervous system (ANS) phenotype in two GAN knockout (KO) mouse models. Little is known about ANS involvement in GAN in humans, but autonomic signs and symptoms are commonly reported in early childhood.
Routine histology and immunohistochemistry was performed on GAN KO mouse specimens taken at various ages. Enteric dysfunction was assessed by quantifying the frequency, weight, and water content of defecation in GAN KO mice.
Histological examination of the enteric, parasympathetic and sympathetic ANS of GAN KO mice revealed pronounced and widespread neuronal perikaryal intermediate filament inclusions. These neuronal inclusions served as an easily identifiable, early marker of GAN in young GAN KO mice. Functional studies identified an age-dependent alteration in fecal weight and defecation frequency in GAN KO mice.
For the first time in the GAN KO mouse model, we described the early, pronounced and widespread neuropathologic features involving the ANS. In addition, we provided evidence for a clinical autonomic phenotype in GAN KO mice, reflected in abnormal gastrointestinal function. These findings in GAN KO mice suggest that consideration should be given to ANS involvement in human GAN, especially when considering treatments and patient care.
KeywordsGiant axonal neuropathy Intermediate filaments Gigaxonin Autonomic nervous system Neurodegenerative disease
Compliance with ethical standards
Conflict of interest
The authors declare no conflicts of interest.
- 2.Demir E, Bomont P, Erdem S, Cavalier L, Demirci M, Kose G, Muftuoglu S, Cakar AN, Tan E, Aysun S, Topcu M, Guicheney P, Koenig M, Topaloglu H (2005) Giant axonal neuropathy: clinical and genetic study in six cases. J Neurol Neurosurg Psychiatry 76:825–832. doi: 10.1136/jnnp.2003.035162 CrossRefPubMedPubMedCentralGoogle Scholar
- 3.Pena SD, Opas M, Turksen K, Kalnins VI, Carpenter S (1983) Immunocytochemical studies of intermediate filament aggregates and their relationship to microtubules in cultured skin fibroblasts from patients with giant axonal neuropathy. Euro J Cell Biol 31:227–234Google Scholar
- 4.Ding JQ, Allen E, Wang W, Valle A, Wu C, Nardine T, Cui B, Yi J, Taylor A, Jeon NL, Chu S, So Y, Vogel H, Tolwani R, Mobley W, Yang Y (2006) Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport. Hum Mol Genet 15:1451–1463. doi: 10.1093/hmg/ddl069 CrossRefPubMedGoogle Scholar
- 7.Li ZS, Schmauss C, Cuenca A, Ratcliffe E, Gershon MD (2006) Physiological modulation of intestinal motility by enteric dopaminergic neurons and the D2 receptor: analysis of dopamine receptor expression, location, development, and function in wild-type and knock-out. J Neurosci 26:2798–2807CrossRefPubMedGoogle Scholar
- 11.Taylor TN, Caudle WM, Shepherd KR, Noorian A, Jackson CR, Iuvone PM, Weinshenker D, Greene JG, Miller GW (2009) Nonmotor symptoms of Parkinson’s disease revealed in an animal model with reduced monoamine storage capacity. J Neurosci 29:8103–8113. doi: 10.1523/JNEUROSCI.1495-09.2009 CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Sames L, Moore A, Arnold R, Ekins S (2014) Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy. F1000Res 83:1–27. doi: 10.12688/f1000research.3751.2