Lynch-Godrei, Anisha2019-12-202019-12-202019-12-20http://hdl.handle.net/10393/39989http://dx.doi.org/10.20381/ruor-24228The mouse dystonin gene (Dst; previously Bpag1) yields three tissue specific isoforms of a giant cytoskeletal linker protein, namely the skin isoform dystonin-e, neuronal isoform dystonin-a, and muscle isoform dystonin-b. Through alternative splicing events at the 5’ end of neuronal and muscle transcripts, three further isoforms with unique N-termini are produced (dystonin-a/b1, -a/b2, and -a/b3). Though dystonin-e has long since been known to be the autoantigen responsible for the human skin blistering disease bullous pemphigoid, mutations affecting the neuronal isoforms have emerged as the major determinant in the murine sensory neuropathy dystonia musculorum (Dstdt), and more recently the human disease Hereditary sensory and autonomic neuropathy type VI (HSAN-VI). Here we report an upregulation in autophagy within sensory neurons from two Dstdt alleles: Dstdt-27J mice that are dystonin-a null, and Dstdt-Tg4 mice that lack dystonin-a1 and -a2 but retain dystonin-a3. Whether this upregulation is protective or pathogenic has yet to be determined. It was initially believed that insufficient trafficking of autophagic vesicles to their final site of degradation in lysosomes was impaired, however extensive evaluation of the levels of motor proteins responsible for autophagosome and lysosome trafficking were found to be in appropriate quantities. Interestingly, investigation of microtubule stability as a possible cause for these changes in autophagy showed that defective microtubule stability is not a common pathology of the Dstdt disorder. Only Dstdt-27J mice have reduced microtubule acetylation, which may help explain their shorter lifespan and symptom severity. In Dstdt-Tg4 sensory neurons, the maintenance of microtubule stability was associated with a 3-4 fold increase in dystonin-a3 transcript expression. Subsequent knockdown of this isoform in Dstdt-Tg4 sensory neurons produced a reduction in microtubule acetylation, suggesting that dystonin isoforms may be capable of taking on novel roles to compensate for the loss of other isoforms. Additionally, we also identify gastrointestinal abnormalities including gas accumulation, slowed motility, and reduced microbial richness/evenness in Dstdt mice, which occur independently of enteric nervous system defects. Rather, these gastrointestinal symptoms are most likely linked to an imbalance in sympathetic and parasympathetic input onto the gut. Collectively these findings help shed light on the heterogeneity of the human HSAN-VI disorder, and identify potential targets for therapeutics and symptom relief.enDystoninCytoskeletonNeuroscienceHSAN-VIbpag1Thesis