The Actin-Binding Protein Capulet Genetically Interacts with the Microtubule Motor Kinesin to Maintain Neuronal Dendrite Homeostasis

BACKGROUND: Neurons require precise cytoskeletal regulation within neurites, containing microtubule tracks for cargo transport in axons and dendrites or within synapses containing organized actin. Due to the unique architecture and specialized function of neurons, neurons are particularly susceptible to perturbation of the cytoskeleton. Numerous actin-binding proteins help maintain proper cytoskeletal regulation. METHODOLOGY/PRINCIPAL FINDINGS: From a Drosophila forward genetic screen, we identified a mutation in capulet--encoding a conserved actin-binding protein--that causes abnormal aggregates of actin within dendrites. Through interaction studies, we demonstrate that simultaneous genetic inactivation of capulet and kinesin heavy chain, a microtubule motor protein, produces elongate cofilin-actin rods within dendrites but not axons. These rods resemble actin-rich structures induced in both mammalian neurodegenerative and Drosophila Alzheimer's models, but have not previously been identified by loss of function mutations in vivo. We further demonstrate that mitochondria, which are transported by Kinesin, have impaired distribution along dendrites in a capulet mutant. While Capulet and Cofilin may biochemically cooperate in certain circumstances, in neuronal dendrites they genetically antagonize each other. CONCLUSIONS/SIGNIFICANCE: The present study is the first molecularly defined loss of function demonstration of actin-cofilin rods in vivo. This study suggests that simultaneous, seemingly minor perturbations in neuronal dendrites can synergize producing severe abnormalities affecting actin, microtubules and mitochondria/energy availability in dendrites. Additionally, as >90% of Alzheimer's and Parkinson's cases are sporadic this study suggests mechanisms by which multiple mutations together may contribute to neurodegeneration instead of reliance on single mutations to produce disease

Strategies of Eradicating Glioma Cells: A Multi-Scale Mathematical Model with MiR-451-AMPK-mTOR Control

The cellular dispersion and therapeutic control of glioblastoma, the most aggressive type of primary brain cancer, depends critically on the migration patterns after surgery and intracellular responses of the individual cancer cells in response to external biochemical and biomechanical cues in the microenvironment. Recent studies have shown that a particular microRNA, miR-451, regulates downstream molecules including AMPK and mTOR to determine the balance between rapid proliferation and invasion in response to metabolic stress in the harsh tumor microenvironment. Surgical removal of main tumor is inevitably followed by recurrence of the tumor due to inaccessibility of dispersed tumor cells in normal brain tissue. In order to address this multi-scale nature of glioblastoma proliferation and invasion and its response to conventional treatment, we propose a hybrid model of glioblastoma that analyses spatio-temporal dynamics at the cellular level, linking individual tumor cells with the macroscopic behaviour of cell organization and the microenvironment, and with the intracellular dynamics of miR-451-AMPK-mTOR signaling within a tumour cell. The model identifies a key mechanism underlying the molecular switches between proliferative phase and migratory phase in response to metabolic stress and biophysical interaction between cells in response to fluctuating glucose levels in the presence of blood vessels (BVs). The model predicts that cell migration, therefore efficacy of the treatment, not only depends on oxygen and glucose availability but also on the relative balance between random motility and strength of chemoattractants. Effective control of growing cells near BV sites in addition to relocalization of invisible migratory cells back to the resection site was suggested as a way of eradicating these migratory cells.Publisher PDFPeer reviewe