Investigating the role of HDAC4 in the progression of Parkinson’s Disease in Drosophila melanogaster : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Genetics at Massey University, Manawatu, New Zealand

Abstract

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterised by the progressive loss of nigrostriatal dopaminergic neurons and the accumulation of α-synuclein-rich protein aggregates known as Lewy bodies. While current therapies manage symptoms, they do not halt disease progression, highlighting the urgent need for curative treatments. Emerging evidence suggests Histone Deacetylase 4 (HDAC4) plays a role in the progression of PD. HDAC4 has been detected in Lewy body inclusions and shown to undergo dysregulated nucleocytoplasmic shuttling in the presence of α-synuclein (SNCA), resulting in its nuclear accumulation and the repression of plasticity-related genes. This thesis investigates the role of HDAC4 in PD progression using a Drosophila melanogaster model. I found that HDAC4 overexpression alone mildly impairs locomotor function and nuclear accumulation. However, co-expression of HDAC4 with SNCA results in altered cellular distribution and the formation of large HDAC4 nuclear condensates. These findings suggest that while HDAC4 mislocalisation may contribute to PD pathology, HDAC4 may also play a critical role in maintaining dopaminergic neuron health.