Clinical Autonomic Research

, Volume 26, Issue 4, pp 307–313 | Cite as

Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease

  • Diane Armao
  • Rachel M. Bailey
  • Thomas W. Bouldin
  • Yongbaek Kim
  • Steven J. Gray
Short Communication



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.


Giant axonal neuropathy Intermediate filaments Gigaxonin Autonomic nervous system Neurodegenerative disease 


Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Supplementary material

10286_2016_365_MOESM1_ESM.pdf (318 kb)
Supplementary material 1 (PDF 317 kb)


  1. 1.
    Johnson-Kerner BL, Roth L, Greene JP, Wichterle H, Sproule DM (2009) Giant axonal neuropathy: an updated perspective on its pathology and pathogenesis. Muscle Nerve 50:467–476. doi: 10.1002/mus.24321 CrossRefGoogle Scholar
  2. 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. 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. 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
  5. 5.
    Ganay T, Boizot A, Burrer R, Chauvin JP, Bomont P (2011) Sensory-motor deficits and neurofilament disorganization in gigaxonin-null mice. Mol Neurodegener 6:25. doi: 10.1186/1750-1326-6-25 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Dequen F, Bomont P, Gowing G, Cleveland DW, Julien JP (2008) Modest loss of peripheral axons, muscle atrophy and formation of brain inclusions in mice with targeted deletion of gigaxonin exon 1. J Neurochem 107:253–264. doi: 10.1111/j.1471-4159.2008.05601 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 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
  8. 8.
    Gambarelli D, Hassoun J, Pellissier JF, Livet MO, Pinsard N, Toga M (1977) Giant axonal neuropathy. Involvement of peripheral nerve, myenteric plexus and extra-neuronal area. Acta Neuropathol 39:261–269CrossRefPubMedGoogle Scholar
  9. 9.
    Andersona G, Nooriana AR, Yaylora G, Anithab M, Bernharda D, Srinivasanb S, Greenea JG (2007) Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson’s disease. Exp Neurol 207:4–12. doi: 10.1016/j.expneurol.2007.05.010 CrossRefGoogle Scholar
  10. 10.
    Wang L, Fleming SM, Chesselet MF, Taché Y (2008) Abnormal colonic motility in mice overexpressing human wild-type alpha-synuclein. NeuroReport 19:873–876. doi: 10.1097/WNR.0b013e3282ffda5e CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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
  12. 12.
    Mussche S, Devreese B, Nagabhushan Kalburgi S, Bachaboina L, Fox JC, Shih HJ, Van Coster R, Samulski RJ, Gray SJ (2013) Restoration of cytoskeleton homeostasis after gigaxonin gene transfer for giant axonal neuropathy. Hum Gene Ther 24:209–219. doi: 10.1089/hum.2012.107 CrossRefPubMedGoogle Scholar
  13. 13.
    Roth LA, Marra JD, LaMarca NH, Sproule DM (2015) Measuring disease progression in giant axonal neuropathy: implications for clinical trial design. J Child Neurol 30:741–748. doi: 10.1177/0883073814542946 CrossRefPubMedGoogle Scholar
  14. 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

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Diane Armao
    • 1
    • 2
  • Rachel M. Bailey
    • 3
  • Thomas W. Bouldin
    • 1
  • Yongbaek Kim
    • 4
  • Steven J. Gray
    • 3
    • 5
  1. 1.Department of Pathology and Laboratory MedicineUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.Department of RadiologyUniversity of North Carolina at Chapel HillChapel HillUSA
  3. 3.Gene Therapy CenterUniversity of North Carolina at Chapel HillChapel HillUSA
  4. 4.Research Institute for Veterinary Sciences and Laboratory of Clinical Pathology, College of Veterinary MedicineSeoul National UniversitySeoulSouth Korea
  5. 5.Department of OphthalmologyUniversity of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations