Disease-causing mechanisms described
Mitochondrial dysfunction resulting from genetic defects is a major theme in many forms of HSP and degenerative ataxias.
This study sheds light on the mitochondrial mechanisms at play leading to neurodegeneration and which would be targets for developing treatments.
Degenerative ataxias and hereditary spastic paraplegias (HSPs) form a continuous, often overlapping disease spectrum sharing not only phenotypic features and underlying genes, but also cellular pathways and disease mechanisms.
Mitochondrial metabolism presents a major molecular theme underlying both multiple ataxias and HSPs, thus indicating a heightened vulnerability of Purkinje cells, spinocerebellar tracts, and motor neurons to mitochondrial dysfunction, which is of particular interest for translational approaches. Mitochondrial dysfunction might be the primary (upstream) or secondary (downstream) result of a genetic defect, with underlying genetic defects in nuclear-encoded genes being much more frequent than in mtDNA genes in both, ataxias and HSPs.
Here, we outline the substantial number of ataxias, spastic ataxias and HSPs caused by mutated genes implicated in (primary or secondary) mitochondrial dysfunction, highlighting several key “mitochondrial” ataxias and HSPs which are of particular interest for their frequency, pathogenesis and translational opportunities.
We then showcase prototypic mitochondrial mechanisms by which disruption of these ataxia and HSP genes contributes to Purkinje cells or corticospinal neuron dysfunction, thus elucidating hypotheses on Purkinje cells and corticospinal neuron vulnerability to mitochondrial dysfunction.
SOURCE: Handb Clin Neurol. 2023;194:79-98. doi: 10.1016/B978-0-12-821751-1.00009-9. PMID: 36813322 Copyright © 2023 Elsevier B.V. All rights reserved.
Ataxia and spastic paraplegia in mitochondrial disease
1. Department of Neurodegenerative Diseases, Center for Neurology & Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
2. Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, and Center for Molecular Medicine, University of Cologne, Cologne, Germany.
3. Cambridge Institute for Medical Research and Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.
4. Department of Neurodegenerative Diseases, Center for Neurology & Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.