{"data":{"id":"10.6084/m9.figshare.1496624","type":"dois","attributes":{"doi":"10.6084/m9.figshare.1496624","prefix":"10.6084","suffix":"m9.figshare.1496624","identifiers":[],"alternateIdentifiers":[],"creators":[{"name":"Ferrier, Andrew","nameType":"Personal","givenName":"Andrew","familyName":"Ferrier","affiliation":[],"nameIdentifiers":[]},{"name":"Repentigny, Yves De","nameType":"Personal","givenName":"Yves De","familyName":"Repentigny","affiliation":[],"nameIdentifiers":[]},{"name":"Anisha Lynch-Godrei","affiliation":[],"nameIdentifiers":[]},{"name":"Gibeault, Sabrina","nameType":"Personal","givenName":"Sabrina","familyName":"Gibeault","affiliation":[],"nameIdentifiers":[]},{"name":"Walaa Eid","affiliation":[],"nameIdentifiers":[]},{"name":"Kuo, Daniel","nameType":"Personal","givenName":"Daniel","familyName":"Kuo","affiliation":[],"nameIdentifiers":[]},{"name":"Xiaohui Zha","affiliation":[],"nameIdentifiers":[]},{"name":"Kothary, Rashmi","nameType":"Personal","givenName":"Rashmi","familyName":"Kothary","affiliation":[],"nameIdentifiers":[]}],"titles":[{"title":"Disruption in the autophagic process underlies the sensory neuropathy in \u003ci\u003edystonia musculorum\u003c/i\u003e mice"}],"publisher":"Taylor \u0026 Francis","container":{},"publicationYear":2015,"subjects":[{"subject":"Biochemistry"},{"subject":"Cell Biology"},{"subject":"Genetics"},{"subject":"FOS: Biological sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"FOS: Biological sciences","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Molecular Biology"},{"subject":"Neuroscience"},{"subject":"Physiology"},{"subject":"39999 Chemical Sciences not elsewhere classified","subjectScheme":"FOR"},{"subject":"FOS: Chemical sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"FOS: Chemical sciences","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Developmental Biology"},{"subject":"111714 Mental Health","subjectScheme":"FOR"},{"subject":"FOS: Health sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"FOS: Health sciences","subjectScheme":"Fields of Science and Technology (FOS)"}],"contributors":[],"dates":[{"date":"2015-07-30","dateType":"Created"},{"date":"2017-02-14","dateType":"Updated"},{"date":"2015","dateType":"Issued"}],"language":null,"types":{"ris":"DATA","bibtex":"misc","citeproc":"dataset","schemaOrg":"Dataset","resourceType":"Dataset","resourceTypeGeneral":"Dataset"},"relatedIdentifiers":[{"relationType":"IsSupplementTo","relatedIdentifier":"10.1080/15548627.2015.1052207","relatedIdentifierType":"DOI"}],"relatedItems":[],"sizes":["13279898 Bytes"],"formats":[],"version":null,"rightsList":[{"rights":"Creative Commons Attribution 4.0 International","rightsUri":"https://creativecommons.org/licenses/by/4.0/legalcode","schemeUri":"https://spdx.org/licenses/","rightsIdentifier":"cc-by-4.0","rightsIdentifierScheme":"SPDX"}],"descriptions":[{"description":"A homozygous mutation in the \u003ci\u003eDST\u003c/i\u003e (dystonin) gene causes a newly identified lethal form of hereditary sensory and autonomic neuropathy in humans (HSAN-VI). DST loss of function similarly leads to sensory neuron degeneration and severe ataxia in \u003ci\u003edystonia musculorum\u003c/i\u003e (\u003ci\u003eDst\u003c/i\u003e\u003csup\u003e\u003ci\u003edt\u003c/i\u003e\u003c/sup\u003e) mice. DST is involved in maintaining cytoskeletal integrity and intracellular transport. As autophagy is highly reliant upon stable microtubules and motor proteins, we assessed the influence of DST loss of function on autophagy using the \u003ci\u003eDst\u003c/i\u003e\u003csup\u003e\u003ci\u003edt-Tg4\u003c/i\u003e\u003c/sup\u003e mouse model. Electron microscopy (EM) revealed an accumulation of autophagosomes in sensory neurons from these mice. Furthermore, we demonstrated that the autophagic flux was impaired. Levels of LC3-II, a marker of autophagosomes, were elevated. Consequently, \u003ci\u003eDst\u003c/i\u003e\u003csup\u003e\u003ci\u003edt-Tg4\u003c/i\u003e\u003c/sup\u003e sensory neurons displayed impaired protein turnover of autophagosome substrate SQTSM1/p62 and of polyubiquitinated proteins. Interestingly, in a previously described \u003ci\u003eDst\u003c/i\u003e\u003csup\u003e\u003ci\u003edt-Tg4\u003c/i\u003e\u003c/sup\u003e mouse model that is partially rescued by neuronal specific expression of the DST-A2 isoform, autophagosomes, autolysosomes, and damaged organelles were reduced when compared to \u003ci\u003eDst\u003c/i\u003e\u003csup\u003e\u003ci\u003edt-Tg4\u003c/i\u003e\u003c/sup\u003e mutant mice. LC3-II, SQTSM1, polyubiquitinated proteins and autophagic flux were also restored to wild-type levels in the rescued mice. Finally, a significant decrease in DNAIC1 (dynein, axonemal, intermediate chain 1; the mouse ortholog of human DNAI1), a member of the DMC (dynein/dynactin motor complex), was noted in \u003ci\u003eDst\u003c/i\u003e\u003csup\u003e\u003ci\u003edt-Tg4\u003c/i\u003e\u003c/sup\u003e dorsal root ganglia and sensory neurons. Thus, DST-A2 loss of function perturbs late stages of autophagy, and dysfunctional autophagy at least partially underlies \u003ci\u003eDst\u003c/i\u003e\u003csup\u003e\u003ci\u003edt\u003c/i\u003e\u003c/sup\u003e pathogenesis. We therefore conclude that the DST-A2 isoform normally facilitates autophagy within sensory neurons to maintain cellular homeostasis.","descriptionType":"Abstract"}],"geoLocations":[],"fundingReferences":[],"xml":"PD94bWwgdmVyc2lvbj0iMS4wIiBlbmNvZGluZz0iVVRGLTgiPz4KPHJlc291cmNlIHhtbG5zPSJodHRwOi8vZGF0YWNpdGUub3JnL3NjaGVtYS9rZXJuZWwtNCIgeG1sbnM6eHNpPSJodHRwOi8vd3d3LnczLm9yZy8yMDAxL1hNTFNjaGVtYS1pbnN0YW5jZSIgeHNpOnNjaGVtYUxvY2F0aW9uPSJodHRwOi8vZGF0YWNpdGUub3JnL3NjaGVtYS9rZXJuZWwtNCBodHRwOi8vc2NoZW1hLmRhdGFjaXRlLm9yZy9tZXRhL2tlcm5lbC00LjEvbWV0YWRhdGEueHNkIj4KICA8aWRlbnRpZmllciBpZGVudGlmaWVyVHlwZT0iRE9JIj4xMC42MDg0L005LkZJR1NIQVJFLjE0OTY2MjQ8L2lkZW50aWZpZXI+CiAgPGNyZWF0b3JzPgogICAgPGNyZWF0b3I+CiAgICAgIDxjcmVhdG9yTmFtZT5BbmRyZXcgRmVycmllcjwvY3JlYXRvck5hbWU+CiAgICA8L2NyZWF0b3I+CiAgICA8Y3JlYXRvcj4KICAgICAgPGNyZWF0b3JOYW1lPll2ZXMgRGUgUmVwZW50aWdueTwvY3JlYXRvck5hbWU+CiAgICA8L2NyZWF0b3I+CiAgICA8Y3JlYXRvcj4KICAgICAgPGNyZWF0b3JOYW1lPkFuaXNoYSBMeW5jaC1Hb2RyZWk8L2NyZWF0b3JOYW1lPgogICAgPC9jcmVhdG9yPgogICAgPGNyZWF0b3I+CiAgICAgIDxjcmVhdG9yTmFtZT5TYWJyaW5hIEdpYmVhdWx0PC9jcmVhdG9yTmFtZT4KICAgIDwvY3JlYXRvcj4KICAgIDxjcmVhdG9yPgogICAgICA8Y3JlYXRvck5hbWU+V2FsYWEgRWlkPC9jcmVhdG9yTmFtZT4KICAgIDwvY3JlYXRvcj4KICAgIDxjcmVhdG9yPgogICAgICA8Y3JlYXRvck5hbWU+RGFuaWVsIEt1bzwvY3JlYXRvck5hbWU+CiAgICA8L2NyZWF0b3I+CiAgICA8Y3JlYXRvcj4KICAgICAgPGNyZWF0b3JOYW1lPlhpYW9odWkgWmhhPC9jcmVhdG9yTmFtZT4KICAgIDwvY3JlYXRvcj4KICAgIDxjcmVhdG9yPgogICAgICA8Y3JlYXRvck5hbWU+UmFzaG1pIEtvdGhhcnk8L2NyZWF0b3JOYW1lPgogICAgPC9jcmVhdG9yPgogIDwvY3JlYXRvcnM+CiAgPHRpdGxlcz4KICAgIDx0aXRsZT5EaXNydXB0aW9uIGluIHRoZSBhdXRvcGhhZ2ljIHByb2Nlc3MgdW5kZXJsaWVzIHRoZSBzZW5zb3J5IG5ldXJvcGF0aHkgaW4gJmx0O2kmZ3Q7ZHlzdG9uaWEgbXVzY3Vsb3J1bSZsdDsvaSZndDsgbWljZTwvdGl0bGU+CiAgPC90aXRsZXM+CiAgPGRlc2NyaXB0aW9ucz4KICAgIDxkZXNjcmlwdGlvbiBkZXNjcmlwdGlvblR5cGU9IkFic3RyYWN0Ij4mbHQ7cCZndDtBIGhvbW96eWdvdXMgbXV0YXRpb24gaW4gdGhlICZsdDtpJmd0O0RTVCZsdDsvaSZndDsgKGR5c3RvbmluKSBnZW5lIGNhdXNlcyBhIG5ld2x5IGlkZW50aWZpZWQgbGV0aGFsIGZvcm0gb2YgaGVyZWRpdGFyeSBzZW5zb3J5IGFuZCBhdXRvbm9taWMgbmV1cm9wYXRoeSBpbiBodW1hbnMgKEhTQU4tVkkpLiBEU1QgbG9zcyBvZiBmdW5jdGlvbiBzaW1pbGFybHkgbGVhZHMgdG8gc2Vuc29yeSBuZXVyb24gZGVnZW5lcmF0aW9uIGFuZCBzZXZlcmUgYXRheGlhIGluICZsdDtpJmd0O2R5c3RvbmlhIG11c2N1bG9ydW0mbHQ7L2kmZ3Q7ICgmbHQ7aSZndDtEc3QmbHQ7L2kmZ3Q7Jmx0O3N1cCZndDsmbHQ7aSZndDtkdCZsdDsvaSZndDsmbHQ7L3N1cCZndDspIG1pY2UuIERTVCBpcyBpbnZvbHZlZCBpbiBtYWludGFpbmluZyBjeXRvc2tlbGV0YWwgaW50ZWdyaXR5IGFuZCBpbnRyYWNlbGx1bGFyIHRyYW5zcG9ydC4gQXMgYXV0b3BoYWd5IGlzIGhpZ2hseSByZWxpYW50IHVwb24gc3RhYmxlIG1pY3JvdHVidWxlcyBhbmQgbW90b3IgcHJvdGVpbnMsIHdlIGFzc2Vzc2VkIHRoZSBpbmZsdWVuY2Ugb2YgRFNUIGxvc3Mgb2YgZnVuY3Rpb24gb24gYXV0b3BoYWd5IHVzaW5nIHRoZSAmbHQ7aSZndDtEc3QmbHQ7L2kmZ3Q7Jmx0O3N1cCZndDsmbHQ7aSZndDtkdC1UZzQmbHQ7L2kmZ3Q7Jmx0Oy9zdXAmZ3Q7IG1vdXNlIG1vZGVsLiBFbGVjdHJvbiBtaWNyb3Njb3B5IChFTSkgcmV2ZWFsZWQgYW4gYWNjdW11bGF0aW9uIG9mIGF1dG9waGFnb3NvbWVzIGluIHNlbnNvcnkgbmV1cm9ucyBmcm9tIHRoZXNlIG1pY2UuIEZ1cnRoZXJtb3JlLCB3ZSBkZW1vbnN0cmF0ZWQgdGhhdCB0aGUgYXV0b3BoYWdpYyBmbHV4IHdhcyBpbXBhaXJlZC4gTGV2ZWxzIG9mIExDMy1JSSwgYSBtYXJrZXIgb2YgYXV0b3BoYWdvc29tZXMsIHdlcmUgZWxldmF0ZWQuIENvbnNlcXVlbnRseSwgJmx0O2kmZ3Q7RHN0Jmx0Oy9pJmd0OyZsdDtzdXAmZ3Q7Jmx0O2kmZ3Q7ZHQtVGc0Jmx0Oy9pJmd0OyZsdDsvc3VwJmd0OyBzZW5zb3J5IG5ldXJvbnMgZGlzcGxheWVkIGltcGFpcmVkIHByb3RlaW4gdHVybm92ZXIgb2YgYXV0b3BoYWdvc29tZSBzdWJzdHJhdGUgU1FUU00xL3A2MiBhbmQgb2YgcG9seXViaXF1aXRpbmF0ZWQgcHJvdGVpbnMuIEludGVyZXN0aW5nbHksIGluIGEgcHJldmlvdXNseSBkZXNjcmliZWQgJmx0O2kmZ3Q7RHN0Jmx0Oy9pJmd0OyZsdDtzdXAmZ3Q7Jmx0O2kmZ3Q7ZHQtVGc0Jmx0Oy9pJmd0OyZsdDsvc3VwJmd0OyBtb3VzZSBtb2RlbCB0aGF0IGlzIHBhcnRpYWxseSByZXNjdWVkIGJ5IG5ldXJvbmFsIHNwZWNpZmljIGV4cHJlc3Npb24gb2YgdGhlIERTVC1BMiBpc29mb3JtLCBhdXRvcGhhZ29zb21lcywgYXV0b2x5c29zb21lcywgYW5kIGRhbWFnZWQgb3JnYW5lbGxlcyB3ZXJlIHJlZHVjZWQgd2hlbiBjb21wYXJlZCB0byAmbHQ7aSZndDtEc3QmbHQ7L2kmZ3Q7Jmx0O3N1cCZndDsmbHQ7aSZndDtkdC1UZzQmbHQ7L2kmZ3Q7Jmx0Oy9zdXAmZ3Q7IG11dGFudCBtaWNlLiBMQzMtSUksIFNRVFNNMSwgcG9seXViaXF1aXRpbmF0ZWQgcHJvdGVpbnMgYW5kIGF1dG9waGFnaWMgZmx1eCB3ZXJlIGFsc28gcmVzdG9yZWQgdG8gd2lsZC10eXBlIGxldmVscyBpbiB0aGUgcmVzY3VlZCBtaWNlLiBGaW5hbGx5LCBhIHNpZ25pZmljYW50IGRlY3JlYXNlIGluIEROQUlDMSAoZHluZWluLCBheG9uZW1hbCwgaW50ZXJtZWRpYXRlIGNoYWluIDE7IHRoZSBtb3VzZSBvcnRob2xvZyBvZiBodW1hbiBETkFJMSksIGEgbWVtYmVyIG9mIHRoZSBETUMgKGR5bmVpbi9keW5hY3RpbiBtb3RvciBjb21wbGV4KSwgd2FzIG5vdGVkIGluICZsdDtpJmd0O0RzdCZsdDsvaSZndDsmbHQ7c3VwJmd0OyZsdDtpJmd0O2R0LVRnNCZsdDsvaSZndDsmbHQ7L3N1cCZndDsgZG9yc2FsIHJvb3QgZ2FuZ2xpYSBhbmQgc2Vuc29yeSBuZXVyb25zLiBUaHVzLCBEU1QtQTIgbG9zcyBvZiBmdW5jdGlvbiBwZXJ0dXJicyBsYXRlIHN0YWdlcyBvZiBhdXRvcGhhZ3ksIGFuZCBkeXNmdW5jdGlvbmFsIGF1dG9waGFneSBhdCBsZWFzdCBwYXJ0aWFsbHkgdW5kZXJsaWVzICZsdDtpJmd0O0RzdCZsdDsvaSZndDsmbHQ7c3VwJmd0OyZsdDtpJmd0O2R0Jmx0Oy9pJmd0OyZsdDsvc3VwJmd0OyBwYXRob2dlbmVzaXMuIFdlIHRoZXJlZm9yZSBjb25jbHVkZSB0aGF0IHRoZSBEU1QtQTIgaXNvZm9ybSBub3JtYWxseSBmYWNpbGl0YXRlcyBhdXRvcGhhZ3kgd2l0aGluIHNlbnNvcnkgbmV1cm9ucyB0byBtYWludGFpbiBjZWxsdWxhciBob21lb3N0YXNpcy4mbHQ7L3AmZ3Q7PC9kZXNjcmlwdGlvbj4KICA8L2Rlc2NyaXB0aW9ucz4KICA8c3ViamVjdHM+CiAgICA8c3ViamVjdD5CaW9jaGVtaXN0cnk8L3N1YmplY3Q+CiAgICA8c3ViamVjdD5DZWxsIEJpb2xvZ3k8L3N1YmplY3Q+CiAgICA8c3ViamVjdD5HZW5ldGljczwvc3ViamVjdD4KICAgIDxzdWJqZWN0Pk1vbGVjdWxhciBCaW9sb2d5PC9zdWJqZWN0PgogICAgPHN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