Title: HAT Tip60 restores learning and memory defects in ALS Drosophila model
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that attacks motor neurons in the brain and spinal cord, leading to paralysis, locomotive defects, and cognitive impairments. Epigenetic studies have discovered a handful of genes linked to ALS. More importantly, such studies have shown that decreased histone acetyltransferase (HAT) activity, increased histone deacetylase (HDAC) activity, or overexpression of critical genes lead to the onset of ALS. Tip60, an important HAT greatly studied in Alzheimer’s disease (AD) in our lab (The Elefant Lab), has been shown to have potential neuroprotective roles in learning, memory, locomotion, synaptic plasticity, and axonal transport and outgrowth. Here, we investigated if increasing Tip60 HAT levels rescues cognitive impairments, as seen in the AD model, in Drosophila ALS model that overexpresses Vap-33-1, a VAPB protein homolog found in humans that is associated with ALS. We hypothesized that increasing Tip60 HAT levels will rescue ALS-related cognitive impairments in the Drosophila third instar larvae. To test this hypothesis, we carried out a single odor paradigm for olfactory associative learning using sucrose as the gustatory reinforcer and Linalool as the associative odor. The same paradigm was used to study short-term and long-term memory after the larvae completed the olfactory associative learning in order to investigate for any memory impairments. We show that ALS third instar larvae exhibited defects in learning and short-term memory. Importantly, these impairments were partially rescued by increasing Tip60 HAT levels. Together, our findings suggest a neuroprotective role for Tip60 in restoring short-term memory defects seen in ALS Drosophila larvae.
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that attacks motor neurons in the brain and spinal cord, leading to paralysis, locomotive defects, and cognitive impairments. Epigenetic studies have discovered a handful of genes linked to ALS. More importantly, such studies have shown that decreased histone acetyltransferase (HAT) activity, increased histone deacetylase (HDAC) activity, or overexpression of critical genes lead to the onset of ALS. Tip60, an important HAT greatly studied in Alzheimer’s disease (AD) in our lab (The Elefant Lab), has been shown to have potential neuroprotective roles in learning, memory, locomotion, synaptic plasticity, and axonal transport and outgrowth. Here, we investigated if increasing Tip60 HAT levels rescues cognitive impairments, as seen in the AD model, in Drosophila ALS model that overexpresses Vap-33-1, a VAPB protein homolog found in humans that is associated with ALS. We hypothesized that increasing Tip60 HAT levels will rescue ALS-related cognitive impairments in the Drosophila third instar larvae. To test this hypothesis, we carried out a single odor paradigm for olfactory associative learning using sucrose as the gustatory reinforcer and Linalool as the associative odor. The same paradigm was used to study short-term and long-term memory after the larvae completed the olfactory associative learning in order to investigate for any memory impairments. We show that ALS third instar larvae exhibited defects in learning and short-term memory. Importantly, these impairments were partially rescued by increasing Tip60 HAT levels. Together, our findings suggest a neuroprotective role for Tip60 in restoring short-term memory defects seen in ALS Drosophila larvae.