Axon-Specific Mitochondrial Pathology in SPG11 Alpha Motor Neurons

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 mo...

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Bibliographic Details
Published in:Frontiers in neuroscience 2021-07, Vol.15, p.680572-680572
Main Authors: Güner, Fabian, Pozner, Tatyana, Krach, Florian, Prots, Iryna, Loskarn, Sandra, Schlötzer-Schrehardt, Ursula, Winkler, Jürgen, Winner, Beate, Regensburger, Martin
Format: Article
Language:English
Subjects:
alpha motor neuron
Axonal transport
Axons
Cell culture
Degeneration
Embryo cells
Fibroblasts
Genes
Hereditary spastic paraplegia
induced pluripotent stem cells
Intellectual disabilities
Membrane potential
Microfluidics
Mitochondria
Morphology
Motor neurons
Neurons
Neuroscience
Pluripotency
Pyramidal tracts
Spasticity
SPG11
Stem cells
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Summary: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.
ISSN:1662-453X
1662-4548
1662-453X
DOI:10.3389/fnins.2021.680572