| First Author | Gorski K | Year | 2023 |
| Journal | Front Mol Neurosci | Volume | 16 |
| Pages | 1175851 | PubMed ID | 37251643 |
| Mgi Jnum | J:346331 | Mgi Id | MGI:7487048 |
| Doi | 10.3389/fnmol.2023.1175851 | Citation | Gorski K, et al. (2023) Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice. Front Mol Neurosci 16:1175851 |
| abstractText | The involvement of mitochondrial dysfunction in cystatin B (CSTB) deficiency has been suggested, but its role in the onset of neurodegeneration, myoclonus, and ataxia in the CSTB-deficient mouse model (Cstb(-/-)) is yet unknown. CSTB is an inhibitor of lysosomal and nuclear cysteine cathepsins. In humans, partial loss-of-function mutations cause the progressive myoclonus epilepsy neurodegenerative disorder, EPM1. Here we applied proteome analysis and respirometry on cerebellar synaptosomes from early symptomatic (Cstb(-/-)) mice to identify the molecular mechanisms involved in the onset of CSTB-deficiency associated neural pathogenesis. Proteome analysis showed that CSTB deficiency is associated with differential expression of mitochondrial and synaptic proteins, and respirometry revealed a progressive impairment in mitochondrial function coinciding with the onset of myoclonus and neurodegeneration in (Cstb(-/-)) mice. This mitochondrial dysfunction was not associated with alterations in mitochondrial DNA copy number or membrane ultrastructure. Collectively, our results show that CSTB deficiency generates a defect in synaptic mitochondrial bioenergetics that coincides with the onset and progression of the clinical phenotypes, and thus is likely a contributor to the pathogenesis of EPM1. |
