Research Grant - 2023

Watch Dr Karissa Barthelson accept the research grant award and hear a bit about the project.

Project Summary:

Dementia is not only a disease of the elderly. Every 1 in 2,800 children are born with a genetic disorder which causes childhood dementia. Sanfilippo syndrome, among these genetic disorders, is particularly tragic and currently has no cure. Children born with Sanfilippo syndrome seem to develop typically during their early years, only to face a loss of developmental milestones from approximately two years of age. In the years following, neurodegeneration begins to onset which ultimately leads to a heartbreaking loss of life. At the cellular level in the Sanfilippo brain, many problems are occurring. Some of these problems appear similar to those which occur in Alzheimer’s disease, the most common form of dementia. However, a thorough comparison of these diseases has not been performed.

This study will utilise our zebrafish models of these diseases to compare the brain gene expression changes at the level of single cells. To do this, we will use a cutting-edge technique called single-nuclei transcriptomics. This is one of the most sensitive and powerful methods of examining the molecular state of the brain. We will dissect how each of the brain’s many different cell types are altered in these diseases, and whether there are commonalities between them. Identification of common cellular changes between the Alzheimer’s disease and Sanfilippo syndrome models will suggest novel therapeutic approaches which could be beneficial for both diseases.

Outcomes:

This project aimed to produce the first single-nucleus RNA sequencing dataset from zebrafish brains carrying mutations linked to Sanfilippo syndrome (also known as mucopolysaccharidosis IIIB – MPS IIIB) and early-onset familial Alzheimer’s disease (EOfAD). Dr Barthelson and her team hypothesised that the sequencing data would reveal common and distinct cell-type-specific gene expression changes between these two diseases.

The EOfAD-like samples produced a usable dataset, and they were able to detect genetic differences. This included differences in neurotransmitter signalling and gene expression in several different cell types. However, the MPS IIIB samples had poor nuclei recovery, preventing meaningful genetic analysis. As a result, they were not able to compare the two diseases.

Overall, this study demonstrates the feasibility of applying single-nucleus RNA sequencing to adult zebrafish brains and provides the first such dataset for EOfAD-like models. The detection of cell-type-specific transcriptomic changes in EOfAD-like fish supports the biological relevance of this model for studying neurodegeneration. However, the limited recovery from MPS IIIB brains highlights a critical barrier to transcriptomic analysis in this disease model. Future work using improved techniques of the Parse Biosciences platform will allow Dr Barthelson and her team to dissect the changes in this model and the commonalities with EOfAD.

Outcomes submitted May 2025.