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DISC1 causes associative memory and neurodevelopmental defects in fruit flies
K Furukubo-Tokunaga1, K Kurita1, K Honjo1
1Life and Environmental Sciences, Institute of Biological Sciences, University of Tsukuba, Tsukuba, Japan.
Molecular Psychiatry
|March 16, 2016
Summary
Human DISC1 protein in fruit flies impairs memory and neural development. Specific protein domains are crucial for these effects, highlighting DISC1
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Disrupted-in-Schizophrenia 1 (DISC1) is an intracellular scaffold protein implicated in neural development.
- DISC1 is associated with diverse mental disorders and interacts with various binding partners.
- Understanding DISC1 function in a genetically tractable system is crucial for elucidating its role in neural processes.
Purpose of the Study:
- To investigate the function of human DISC1 in the nervous system of fruit flies (Drosophila melanogaster).
- To identify specific domains of DISC1 responsible for its effects on memory, neural branching, and synaptogenesis.
- To explore the interaction between DISC1 and its homolog of Dysbindin (DTNBP1).
Main Methods:
- Expression of human DISC1 in Drosophila melanogaster.
- Analysis of DISC1 localization in developing fly neurons.
- Behavioral assays for associative memory.
- Examination of axonal and dendritic branching in mushroom body neurons.
- Investigation of synaptogenesis at neuromuscular junctions.
- Use of deletion/mutation constructs to map functional domains.
- Co-immunoprecipitation to study protein-protein interactions.
Main Results:
- Overexpression of DISC1 impairs associative memory and suppresses axonal/dendritic branching of mushroom body neurons.
- Specific domains (amino-terminal 46-290, carboxyl 598-854, and 349-402) are critical for memory and axonal branching suppression.
- DISC1 suppresses glutamatergic synaptogenesis, with domains 403-596 and 349-402 being important.
- Nuclear localization signal 1 (NLS1) is dispensable for memory and axonal branching but required for dendritic branching suppression.
- DISC1 directly interacts with the Drosophila homolog of Dysbindin (DTNBP1).
Conclusions:
- DISC1 plays a significant role in regulating neural development, including memory, neuronal morphology, and synapse formation in Drosophila.
- Distinct protein domains of DISC1 mediate specific functions, suggesting complex regulatory mechanisms.
- The interaction between DISC1 and DTNBP1 is important for synaptic function.
