Disruption of the MAP1B-related Protein FUTSCH Leads to Changes in the Neuronal Cytoskeleton, Axonal Transport Defects, and Progressive Neurodegeneration inDrosophila

Abstract

The elaboration of neuronal axons and dendrites is dependent on a functional cytoskeleton. Cytoskeletal components have been shown to play a major role in the maintenance of the nervous system through adulthood, and changes in neurofilaments and microtubule-associated proteins (MAPs) have been linked to a variety of neurodegenerative diseases. Here we show that Futsch, the fly homolog of MAP1B, is involved in progressive neurodegeneration. Although Futsch is widely expressed throughout the CNS, degeneration in futsch(olk) primarily occurs in the olfactory system and mushroom bodies. Consistent with the predicted function of Futsch, we find abnormalities in the microtubule network and defects in axonal transport. Degeneration in the adult brain is preceded by learning deficits, revealing a neuronal dysfunction before detectable levels of cell death. Futsch is negatively regulated by the Drosophila Fragile X mental retardation gene, and a mutation in this gene delays the onset of neurodegeneration in futsch(olk). A similar effect is obtained by expression of either fly or bovine tau, suggesting a certain degree of functional redundancy of MAPs. The futsch(olk) mutants exhibit several characteristics of human neurodegenerative diseases, providing an opportunity to study the role of MAPs in progressive neurodegeneration within an experimentally accessible, in vivo model system.

Impaired hippocampal long-term potentiation in microtubule-associated protein 1B-deficient mice

“…Two recent studies demonstrating that MAP1B disruption destabilizes and disorganizes axonal microtubules (da Cruz et al, 2005;Tint et al, 2005), further support our assertion that MAP1B is critical for cytoskeletal rearrangements. Furthermore, because our studies were carried out on slices from MAP1Bþ/À mice that express half the normal amount of MAP1B, LTP seems to be sensitive to gene dosage effects.…”

“…The induction of LTP is associated with both rapid and enduring changes in neuronal dendritic morphology (Muller et al, 2002;Harris et al, 2003), including long-lasting increases in dendritic spine head volume and postsynaptic density area, and marked shifts in the proportions of different spine types (Fifkova and Morales, 1992;Engert and Bonhoeffer, 1999;Popov et al, 2004). Neuronal morphogenesis occurs as a result of cytoskeletal alterations including the reorganization of microtubules (Teng et al, 2001;da Cruz et al, 2005;Tint et al, 2005). Arrays of microtubules are stabilized by microtubule-associated proteins (MAPs), whose binding is regulated by their state of phosphorylation (Mitchison and Kirschner, 1988;Matus, 1991;Avila et al, 1994;Riederer, 1995;Sanchez et al, 1997), suggesting that phosphorylation of MAPs may play a role in microtubule destabilization necessary for the expression of LTP (Fukunaga et al, 1995;Quinlan and Halpain, 1996;Sanchez et al, 1997;Vaillant et al, 2002).…”

The B′ Protein Phosphatase 2A Regulatory Subunitwell-roundedRegulates Synaptic Growth and Cytoskeletal Stability at theDrosophilaNeuromuscular Junction

“…Similar Futsch localization is associated with a destabilized microtubule cytoskeleton and defects in synaptic growth (Roos et al, 2000;Zhang et al, 2001;da Cruz et al, 2005). Phosphorylation dynamics are known to play an important role in cytoskeletal stability.…”

Drosophila Ringmaker regulates microtubule stabilization and axonal extension during embryonic development

“…For instance, TPPP has been suggested to bundle microtubules in manner similar to that of Tau (DeBonis et al, 2015). In Drosophila neurons, Tau knockdown only shows exacerbated neuronal degeneration when combined with futsch mutations (Bolkan and Kretzschmar, 2014;da Cruz et al, 2005). We hypothesize that Ringer acts in a manner similar to Tau.…”