HAT Tip60 restores learning and memory defects in ALS Drosophila model
Visha Parmar, Priyalakshmi Panikker*, Mariah Beaver*, Felice Elefant*
*Co-mentors, Department of Biology, Drexel University, Philadelphia, PA
In the realm of learning and memory, histone acetylation is a form of epigenetic modification that plays an important role in modulating gene expression for proper neuronal development and cognitive function. Tip60, an important HAT that has been greatly studied in Alzheimer’s Disease (AD) Drosophila model in our lab, is crucial for proper learning and memory, locomotion, synaptic plasticity, axonal transport and outgrowth. It was shown that disruptions of HAT Tip60 levels in the AD Drosophila model resulted in cognitive impairments and by increasing Tip60 levels, there was a rescue of these impairments. Whether this is also seen in other neurodegenerative diseases such as Drosophila models of Parkinson’s disease, Huntington’s Disease, and Amyotrophic Lateral Sclerosis (ALS) is still unclear. It was recently discovered by our lab that there are similar epigenetic alterations in the HD and PD model that contribute to defects in learning and memory. These cognitive impairments were rescued by Tip60. What remains to be seen is whether the ALS model exhibits similar cognitive impairments and if it can be rescued by Tip60.
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 cognitiveimpairments 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.
Visha Parmar, Priyalakshmi Panikker*, Mariah Beaver*, Felice Elefant*
*Co-mentors, Department of Biology, Drexel University, Philadelphia, PA
In the realm of learning and memory, histone acetylation is a form of epigenetic modification that plays an important role in modulating gene expression for proper neuronal development and cognitive function. Tip60, an important HAT that has been greatly studied in Alzheimer’s Disease (AD) Drosophila model in our lab, is crucial for proper learning and memory, locomotion, synaptic plasticity, axonal transport and outgrowth. It was shown that disruptions of HAT Tip60 levels in the AD Drosophila model resulted in cognitive impairments and by increasing Tip60 levels, there was a rescue of these impairments. Whether this is also seen in other neurodegenerative diseases such as Drosophila models of Parkinson’s disease, Huntington’s Disease, and Amyotrophic Lateral Sclerosis (ALS) is still unclear. It was recently discovered by our lab that there are similar epigenetic alterations in the HD and PD model that contribute to defects in learning and memory. These cognitive impairments were rescued by Tip60. What remains to be seen is whether the ALS model exhibits similar cognitive impairments and if it can be rescued by Tip60.
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 cognitiveimpairments 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.