Epigenetic Mediated Neuroprotection by Tip60 in a Drosophila Model of ALS

Histone acetylation is a type of epigenetic modification that is regulated by histone acetyltransferases (HAT) and histone deacetylases (HDAC). Disruption of HAT/HDAC balance in the brain contributes to synaptic and cognitive deficits found in Alzheimer's disease (AD). ALS is characterized by motor neuron degeneration in the CNS, leading to paralysis, locomotive, and cognitive deficits. This study provides an insight on Tip60 imbalance as a general early feature in ALS and its neuroprotective role in protecting against ALS associated deficits. The GAL4/UAS system was used to target the expression of a transgene. 201Y is a mushroom body (MB) GAL4 driver expressing Vap-33-1, the ALS model used here, in MB of Drosophila. Data was obtained by conducting larva motor function assay, speed test, learning and memory assay, and imaging larval NMJs located between muscles 6/7 in the segment A3 using Olympus FV1000 Fluoview laser scanning confocal microscope. We found that cognitive decline was recapitulated in ALS larvae through motor function assay and learning and memory assay. This cognitive decline may be due to a misregulation of synaptic plasticity genes in early stages of ALS.

Defects in synaptic morphology were observed. Increasing HAT Tip60 levels shows a partial rescue in locomotor

defects, learning, and memory defects in ALS larvae compared to wild type control larvae.
This suggests a neuroprotective role of Tip60 in restoring locomotor and cognitive defects in ALS larvae.