Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Mouse.

By means of a proteomic approach, we assessed the pathways involved in cerebellar neurodegeneration in a mouse model , ) of mitochondrial disorder. A differential proteomic profile study (iTRAQ) was performed in cerebellum homogenates of male and wild-type (WT) mice 8 weeks after the onset of clear symptoms of ataxia in the mice (aged 5.2 ± 0.2 and 5.3 ± 0.1 months for WT and , respectively), followed by a biochemical validation of the most relevant changes. Additional groups of 2-, 3- and 6-month-old WT and mice were analyzed to assess the disease progression on the proteins altered in the proteomic study. The proteomic analysis showed that beyond the expected deregulation of oxidative phosphorylation, the cerebellum of mice showed a marked astroglial activation together with alterations in Ca homeostasis and neurotransmission, with an up- and downregulation of GABAergic and glutamatergic neurotransmission, respectively, and the downregulation of cerebellar "long-term depression", a synaptic plasticity phenomenon that is a major player in the error-driven learning that occurs in the cerebellar cortex. Our study provides novel insights into the mechanisms associated with cerebellar degeneration in the mouse model, including a complex deregulation of neuroinflammation, oxidative phosphorylation and glutamate, GABA and amino acids' metabolism.