Rescue of mitochondrial and neurite pathology in SPG7 hereditary spastic paraplegia patient-derived cortical neurons

Neubauer D, Kaißer C, Krumm L, Börstler T, Metzner KL, Al Hamad T, Böttcher M, Geißler S, Prots I, Arnold P, Mougiakakos D, Winkler J, Winner B, Regensburger M (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Brain Communications Oxford University Press

Book Volume: 8

Article Number: fcag219

Journal Issue: 3

DOI: 10.1093/braincomms/fcag219

Abstract

Biallelic pathogenic variants in SPG7 are a frequent cause of hereditary spastic paraplegia leading to progressive disability due to a length-dependent degeneration of cerebellar and cortical projection neurons. While underlying mechanisms have been linked to impaired mitochondrial function, no disease-modifying therapy is available. We generated induced pluripotent stem cell–derived cortical neurons from SPG7 patients with non-sense or truncating variants and from matched controls. We performed detailed phenotyping of neuronal differentiation, as well as mitochondrial and neuritic morphology and function. We explored the effects of Bz-423, a modulator of the mitochondrial permeability transition pore, as a potential rescue of SPG7-specific cellular phenotypes. We successfully differentiated SPG7 patient-derived neurons, without quantitative differences in differentiation compared with controls. However, we delineate neurite-specific aberrations of mitochondrial morphology and ultrastructure. Moreover, anterograde axonal mitochondrial transport was impaired in SPG7. Exposure to Bz-423 rescued ultrastructural and functional phenotypes. In summary, our data show impaired neuritic mitochondria in a patient-specific human model, and we here demonstrate for the first time beneficial effects of Bz-423 on neuritic ultrastructure and function in a human neuronal SPG7 system. Moreover, we identify the mitochondrial permeability transition pore as a molecular target to rescue phenotypes also in carriers of non-sense or truncating SPG7 variants.

Authors with CRIS profile

David Neubauer Lehrstuhl für Neurologie Carlotta Kaißer Department of Molecular Neurology Laura Krumm Professur für Molekulare Neurologie Tom Börstler Professur für Stammzell-Modelle seltener neuraler Erkrankungen Klara Luise Metzner Professur für Stammzell-Modelle seltener neuraler Erkrankungen Simon Geißler Lehrstuhl für Neurologie Iryna Prots Interdisziplinäres Zentrum für Klinische Forschung IZKF-Förderlinien Philipp Arnold Lehrstuhl für Funktionelle und Klinische Anatomie Jürgen Winkler Professur für Molekulare Neurologie Beate Winner Professur für Stammzell-Modelle seltener neuraler Erkrankungen Martin Regensburger Department of Neurology

Involved external institutions

Otto-von-Guericke-Universität Magdeburg DE Germany (DE)

How to cite

APA:

Neubauer, D., Kaißer, C., Krumm, L., Börstler, T., Metzner, K.L., Al Hamad, T.,... Regensburger, M. (2026). Rescue of mitochondrial and neurite pathology in SPG7 hereditary spastic paraplegia patient-derived cortical neurons. Brain Communications, 8(3). https://doi.org/10.1093/braincomms/fcag219

MLA:

Neubauer, David, et al. "Rescue of mitochondrial and neurite pathology in SPG7 hereditary spastic paraplegia patient-derived cortical neurons." Brain Communications 8.3 (2026).

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