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

Abstract

PURPOSE 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Gigaxonin glycosylation regulates intermediate filament turnover and may impact giant axonal neuropathy etiology or treatment

“…Primary fibroblasts from GAN patients have been powerful tools for dissecting the functional impact of gigaxonin mutants, but they are genetically heterogeneous and often exhibit variable IF phenotypes (e.g., 3%-15% of cells displaying ovoid aggregates), which may confound the interpretation of some experiments (8,50). Mouse models of GAN have also been valuable but exhibit less-severe neurodegeneration than do humans, suggesting potentially important species-dependent differences (51)(52)(53). Therefore, we used CRISPR genome engineering to ablate endogenous gigaxonin expression in human cells, establishing GAN -/systems that reliably recapitulate cellular GAN disease phenotypes and permit functional tests of gigaxonin mutants.…”

“…Our loss-of-function GAN models display classical ovoid vimentin aggregates in a consistent and robust manner, enabling genetic complementation experiments to cells have heterogeneous genetic backgrounds and display incompletely penetrant IF phenotypes (e.g., 3%-15% of cells displaying ovoid aggregates), which may complicate the interpretation of mechanistic and functional studies. GAN -/mice have also been powerful systems but do not fully phenocopy human GAN symptoms, suggesting important species-dependent differences (13,(51)(52)(53). Using CRISPR-mediated gene deletion, we developed GAN -/models in both GAN-relevant human fibroblast and neuroblastoma cell lines (12), in which more than 80% of GAN -/cells display ovoid-shaped vimentin aggregates (Figure 2 and Figure 3).…”

Giant axonal neuropathy: A differential diagnosis of consideration

“…Both gastrointestinal and urinary symptoms in our case may be due to autonomic nervous system involvement, which are documented in animal models. 10 Although correlation between clinical and genetic findings needs further investigation, clinical and radiological features mentioned may be investigated initially in patients from south-eastern Turkey.…”

Advancing the pathologic phenotype of giant axonal neuropathy: early involvement of the ocular lens

“…Three mouse models of GAN have been developed by knocking out part of the endogenous GAN gene [4–6]. All three mouse models mirror the IF dysregulation and widespread nervous system pathology seen in human GAN [7]. Validation of therapeutic efficacy and viral vector delivery systems with these GAN KO models [8] has provided the springboard for the development of a viral vector to be delivered intrathecally in a Phase I gene therapy clinical trial for the treatment of children with GAN [9].…”