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Neurosci."],"abstract":"<jats:p>Pathogenic variants in <jats:italic>SPG11<\/jats:italic> are the most frequent cause of autosomal recessive complicated hereditary spastic paraplegia (HSP). In addition to spastic paraplegia caused by corticospinal degeneration, most patients are significantly affected by progressive weakness and muscle wasting due to alpha motor neuron (MN) degeneration. Mitochondria play a crucial role in neuronal health, and mitochondrial deficits were reported in other types of HSPs. To investigate whether mitochondrial pathology is present in SPG11, we differentiated MNs from induced pluripotent stem cells derived from SPG11 patients and controls. MN derived from human embryonic stem cells and an isogenic SPG11 knockout line were also included in the study. Morphological analysis of mitochondria in the MN soma versus neurites revealed specific alterations of mitochondrial morphology within SPG11 neurites, but not within the soma. In addition, impaired mitochondrial membrane potential was indicative of mitochondrial dysfunction. Moreover, we reveal neuritic aggregates further supporting neurite pathology in SPG11. Correspondingly, using a microfluidic-based MN culture system, we demonstrate that axonal mitochondrial transport was significantly impaired in SPG11. Overall, our data demonstrate that alterations in morphology, function, and transport of mitochondria are an important feature of axonal dysfunction in SPG11 MNs.<\/jats:p>","DOI":"10.3389\/fnins.2021.680572","type":"journal-article","created":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T04:25:31Z","timestamp":1625631931000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Axon-Specific Mitochondrial Pathology in SPG11 Alpha Motor Neurons"],"prefix":"10.3389","volume":"15","author":[{"given":"Fabian","family":"G\u00fcner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana","family":"Pozner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Krach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iryna","family":"Prots","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Loskarn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Schl\u00f6tzer-Schrehardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Winkler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Winner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Regensburger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1002\/cyto.a.20896","article-title":"Quantifying colocalization by correlation: the Pearson correlation coefficient is superior to the Mander\u2019s overlap coefficient.","volume":"77","author":"Adler","year":"2010","journal-title":"Cytometry A?"},{"key":"B2","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/b978-0-444-64076-5.00041-7","article-title":"Hereditary spastic paraplegia.","volume":"148","author":"Blackstone","year":"2018","journal-title":"Handb. 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