UC San Diego

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease caused by a CAG/polyglutamine (polyQ) repeat expansion in the ataxin-7 gene. Adult patient clinical features include cerebellar ataxia, which leads to problems with movement and speech, and retinal degeneration, which leads to blindness. Infants and children with SCA7 present with a much more progressive and severe form of the disease that affects non-neuronal tissues and can lead to multi-organ failure. Mitochondrial dysfunction has been implicated in the pathogenesis and progression of neurodegenerative diseases, but this is yet to be explored in SCA7. SCA7 patients, both adult and juvenile, have similar clinical features to patients with mitochondrial disease. I explored these connections in a mouse model of infantile-onset SCA7 and a novel isogenic stem cell model. I find that SCA7 exhibits mitochondrial dysfunction in both models through mitochondrial fragmentation and decreased metabolic respiration. Purkinje cells in SCA7 mice also have larger individual mitochondria when assessed at an ultrastructural level. These mice exhibit decreases in metabolic substrates, as well, but stem cell-derived neural progenitor cells (NPCs) expressing mutant ataxin-7 do not exhibit any defects in mitochondrial membrane potential (MMP), levels of reactive oxygen species (ROS), or levels of mitochondrial proteins. Ataxin-7 is an integral part of the STAGA transcriptional co-activator complex. Thus, I hypothesized that this dysfunction was caused by transcriptional dysregulation of nuclear genes important to mitochondrial function. Through an assessment of gene expression in SCA7 mice, I did not find evidence for global transcriptional dysregulation of gene sets encoding mitochondrial proteins, but I did identify a decrease in the expression of the gene encoding nicotinamide nucleotide adenylyltransferase 1 (NMNAT1), an enzyme critical for the synthesis of nicotinamide adenine dinucleotide (NAD+). Mass spectrometry analysis of NAD+ in SCA7 mice revealed a significant reduction in NAD+ levels in the cerebellum. While further studies are needed to ascertain the mechanistic implications of these findings, this work establishes mitochondrial dysfunction as a key feature of the molecular pathology of SCA7.