Brain region specific molecular changes in SCA1

There have been a number of studies in diverse subsets in neurodegenerative disorders using large scale transcriptomics and proteomics to access brain region-dependent molecular alterations. Through these studies gene clusters related to transcription, chromatin factors and mitochondria that appear to be specific to sub-brain regions including the cortex and striatum were identified.

Spinocerebellar ataxia type 1 (SCA1) is a fatal late-onset neurodegenerative disorder that is characterized by impaired motor coordination and balance, and also atrophy and loss of Purkinje cells in the cerebellum and cell death in the inferior olive identified in post mortem human tissue. A majority of previous studies in SCA1 has focused on neurodegenerative defects and their impacts on the cerebellum, but other brain affected regions such as the inferior olive have remained largely unstudied.

Thus, scientists at the Yale School of Medicine: Dr. Terri Driessen, Paul Lee and led by Professor Janghoo Lim set up a study to investigate the molecular and pathological signatures of the inferior olive with thorough comparison in two different SCA1 mouse models, and further identify similarities and differences in the gene expression profile between the inferior olive and the cerebellum. The research work is published in the journal eLife.

The research team discovered that at the early stage of SCA1 disease (i.e. 12 weeks old), in the Atxn1 knock-in (Atxn1^154Q/2Q) inferior olive, a total of 204 genes were differentially regulated, with 43 annotated transcripts up-regulated and 161 down-regulated. Functional annotation clustering identified the defense response, which is the molecular response to a foreign body or injury, as the most highly enriched pathway, with other pathways associated with the defensive response being the immune response and the defense response to the virus. These findings may lead to new drug targets in the future.

The findings of Professor Janghoo Lim and his research team show for the first time that there are specific biological pathways enriched in the less studied SCA1 affected tissue, the inferior olive, and that there are intrinsic molecular differences between two affected tissues in SCA1 (the inferior olive and the cerebellum). This will inspire new ideas for targeting the disease in the two brain regions for better effective treatment.

These findings also show that there are different mechanisms of degeneration at work in the two brain tissues and suggest that further studies could be conducted to identify possible mechanism of degeneration in other parts of the brain.