Mitochondrial dysfunction plays a significant role in neurodegenerative disease including ataxias and other movement disorders, particularly those marked by progressive degeneration in the cerebellum. In this study, we investigate the role of mitochondrial oxidative phosphorylation (OXPHOS) deficits in cerebellar tissue of a Purkinje cell-driven spinocerebellar ataxia type 1 (SCA1) mouse. Using RNA sequencing transcriptomics, OXPHOS complex assembly analysis and oxygen consumption assays, we report that in the presence of mutant polyglutamine-expanded ataxin-1, SCA1 mice display deficits in cerebellar OXPHOS complex I (NADH-coenzyme Q oxidoreductase). Complex I genes are upregulated at the time of symptom onset and upregulation persists into late stage disease; yet, functional assembly of complex I macromolecules are diminished and oxygen respiration through complex I is reduced. Acute treatment of postsymptomatic SCA1 mice with succinic acid, a complex II (succinate dehydrogenase) electron donor to bypass complex I dysfunction, ameliorated cerebellar OXPHOS dysfunction, reduced cerebellar pathology and improved motor behavior. Thus, exploration of mitochondrial dysfunction and its role in neurodegenerative ataxias, and warrants further investigation.

The temporal discrimination threshold (TDT) is the shortest interstimulus interval at which a subject can perceive successive stimuli as separate. To investigate the effects of aging on TDT, we studied tactile TDT using the method of limits with 120% of sensory threshold in each hand for each of 100 healthy volunteers, equally divided among males and females, across ten age groups, from 18 to 79 years. Linear regression analysis showed that age was significantly related to left hand mean, right hand mean and mean of two hands with R-square equal to 0.08, 0.164 and 0.132, respectively. Reliability analysis indicated that the three measures had fair-to-good reliability (intraclass correlation coefficient: 0.4-0.8). We conclude that TDT is affected by age and has fair-to-good reproducibility using our technique.

No abstract

Proteoglycans (PGs) are a diverse group of highly glycosylated macromolecules that are implicated in the development and maintenance of neuronal circuitry. With its highly ordered, layered structure, the retina ideally serves to define the synthesis, processing, and distribution of these molecules within a specific cellular subpopulation. In retinal sections, monoclonal antibody (MAb) 6A2 immunostained a horizontal cell-specific antigen. Antigen 6A2 was expressed within abundant processes in the outer plexiform layer and in rare neurites that extend across the inner nuclear layer to the inner plexiform layer. Ultrastructurally, the antigen was localized to cisternae within horizontal cell somata, along tubulovesicular structures in dendrites, and in the perisynaptic space encircling presynaptic terminals of the cone photoreceptor triad. These findings suggest that this PG is synthesized within the horizontal cells, transported to the terminals, and released into the extracellular spaces just proximal to the synapse. Based on the focal stain in the adjacent photoreceptor cell, it is possible that antigen is pinocytosed by this cell and is concentrated at the ribbon synapse. In Western immunoblots of retinal homogenates, MAb 6A2 recognized a heterogeneous chondroitin sulfate (CS) PG (CSPG) of approximately 400-500 kDa. After sequential enzymatic removal of CS glycosaminoglycans, a major broad band of 300-500 kDa was identified by MAb 1B5, which detects CSPGs that bear uronic acid linked to unsulfated N-acetylgalactosamine as the initial disaccharide in the CS chain. Localization of this PG around presynaptic terminals of the horizontal neuron and at the ribbon synapse suggests that it may play a modulatory and sustaining role at the synapse.