Axon-Specific Mitochondrial Pathology in SPG11 Alpha Motor Neurons

Güner F, Pozner T, Krach F, Prots I, Loskarn S, Schlötzer-Schrehardt U, Winkler J, Winner B, Regensburger M (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Frontiers in Neuroscience Frontiers Research Foundation / Frontiers Media

Book Volume: 15

Article Number: 680572

URI: https://www.frontiersin.org/articles/10.3389/fnins.2021.680572/full

DOI: 10.3389/fnins.2021.680572

Abstract

Pathogenic variants in SPG11 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.

Authors with CRIS profile

Fabian Güner Department of Neurology Tatyana Pozner Professur für Stammzell-Modelle seltener neuraler Erkrankungen Iryna Prots Professur für Stammzell-Modelle seltener neuraler Erkrankungen Ursula Schlötzer-Schrehardt Medizinische Fakultät Jürgen Winkler Professur für Molekulare Neurologie Beate Winner Professur für Stammzell-Modelle seltener neuraler Erkrankungen Martin Regensburger Professur für Stammzell-Modelle seltener neuraler Erkrankungen

Related research project(s)

Bavarian Research Association Interaction of Human Brain Cells (ForInter) March 1, 2019 - Dec. 31, 2023 N2: Sensorbasiertes Monitoring der Gangstörung bei HSP-Patienten mit Umsetzung im AlltagN7: Identifikation der Veränderungen im GSK3-Signalweg bei autosomal-rezessiven Typen der kompliziertenHSP anhand von neuralen Modellen aus induziert-pluripotenten Stammzellen (TreatHSP) N2: Sensorbasiertes Monitoring der Gangstörung bei HSP-Patienten mit Umsetzung im AlltagN7: Identifikation der Veränderungen im GSK3-Signalweg bei autosomal-rezessiven Typen der kompliziertenHSP anhand von neuralen Modellen aus induziert-pluripotenten Stammzellen May 1, 2019 - Jan. 31, 2023

How to cite

APA:

Güner, F., Pozner, T., Krach, F., Prots, I., Loskarn, S., Schlötzer-Schrehardt, U.,... Regensburger, M. (2021). Axon-Specific Mitochondrial Pathology in SPG11 Alpha Motor Neurons. Frontiers in Neuroscience, 15. https://doi.org/10.3389/fnins.2021.680572

MLA:

Güner, Fabian, et al. "Axon-Specific Mitochondrial Pathology in SPG11 Alpha Motor Neurons." Frontiers in Neuroscience 15 (2021).

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