Endosomal dysfunction contributes to cerebellar deficits in spinocerebellar ataxia type 6

• Published in: eLife 2023-12, Vol.12
• Main Authors: Cook, Anna A, Leung, Tsz Chui Sophia, Rice, Max, Nachman, Maya, Zadigue-Dube, Élyse, Watt, Alanna Jean
• Format: Article
• Language: English
• Subjects: Ataxia; BDNF–TrkB signaling; Brain-derived neurotrophic factor; Cell membranes; cellular trafficking; Cerebellum; Disease; early endosomes; Endosomes; Genes; Kinases; Ligands; Localization; lysosome; Lysosomes; Neurodegeneration; Neuroscience; Ontology; Pathophysiology; Protein turnover; Purkinje cells; Spinocerebellar ataxia; Therapeutic targets; transcriptomics; TrkB receptors; Tropomyosin; Tropomyosin kinase
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.90510

Spinocerebellar ataxia type 6 (SCA6) is a rare disease that is characterized by cerebellar dysfunction. Patients have progressive motor coordination impairment, and postmortem brain tissue reveals degeneration of cerebellar Purkinje cells and a reduced level of cerebellar brain-derived neurotrophic factor (BDNF). However, the pathophysiological changes underlying SCA6 are not fully understood. We carried out RNA-sequencing of cerebellar vermis tissue in a mouse model of SCA6, which revealed widespread dysregulation of genes associated with the endo-lysosomal system. Since disruption to endosomes or lysosomes could contribute to cellular deficits, we examined the endo-lysosomal system in SCA6. We identified alterations in multiple endosomal compartments in the Purkinje cells of SCA6 mice. Early endosomes were enlarged, while the size of the late endosome compartment was reduced. We also found evidence for impaired trafficking of cargo to the lysosomes. As the proper functioning of the endo-lysosomal system is crucial for the sorting and trafficking of signaling molecules, we wondered whether these changes could contribute to previously identified deficits in signaling by BDNF and its receptor tropomyosin kinase B (TrkB) in SCA6. Indeed, we found that the enlarged early endosomes in SCA6 mice accumulated both BDNF and TrkB. Furthermore, TrkB recycling to the cell membrane in recycling endosomes was reduced, and the late endosome transport of BDNF for degradation was impaired. Therefore, mis-trafficking due to aberrant endo-lysosomal transport and function could contribute to SCA6 pathophysiology through alterations to BDNF-TrkB signaling, as well as mishandling of other signaling molecules. Deficits in early endosomes and BDNF localization were rescued by chronic administration of a TrkB agonist, 7,8-dihydroxyflavone, that we have previously shown restores motor coordination and cerebellar TrkB expression. The endo-lysosomal system is thus both a novel locus of pathophysiology in SCA6 and a promising therapeutic target.