Bosco Daryl A.

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Bosco
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Daryl A.
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ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation

2017-03-08 , Sama, Reddy Ranjith K. , Fallini, Claudia , Gatto, Rodolfo , McKeon, Jeanne E. , Song, Yuyu , Rotunno, Melissa S. , Penaranda, Saul , Abdurakhmanov, Izrail , Landers, John E. , Morfini, Gerardo A. , Brady, Scott T. , Bosco, Daryl A.

Mutations in Fused in Sarcoma/Translocated in Liposarcoma (FUS) cause familial forms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive axonal degeneration mainly affecting motor neurons. Evidence from transgenic mouse models suggests mutant forms of FUS exert an unknown gain-of-toxic function in motor neurons, but mechanisms underlying this effect remain unknown. Towards this end, we studied the effect of wild type FUS (FUS WT) and three ALS-linked variants (G230C, R521G and R495X) on fast axonal transport (FAT), a cellular process critical for appropriate maintenance of axonal connectivity. All ALS-FUS variants impaired anterograde and retrograde FAT in squid axoplasm, whereas FUS WT had no effect. Misfolding of mutant FUS is implicated in this process, as the molecular chaperone Hsp110 mitigated these toxic effects. Interestingly, mutant FUS-induced impairment of FAT in squid axoplasm and of axonal outgrowth in mammalian primary motor neurons involved aberrant activation of the p38 MAPK pathway, as also reported for ALS-linked forms of Cu, Zn superoxide dismutase (SOD1). Accordingly, increased levels of active p38 MAPK were detected in post-mortem human ALS-FUS brain tissues. These data provide evidence for a novel gain-of-toxic function for ALS-linked FUS involving p38 MAPK activation.

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Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase

2013-06-12 , Morfini, Gerardo A. , Bosco, Daryl A. , Brown, Hannah , Gatto, Rodolfo , Kaminska, Agnieszka , Song, Yuyu , Molla, Linda , Baker, Lisa , Marangoni, M. Natalia , Berth, Sarah , Tavassoli, Ehsan , Bagnato, Carolina , Tiwari, Ashutosh , Hayward, Lawrence J. , Pigino, Gustavo F. , Watterson, D. Martin , Huang, Chun-Fang , Banker, Gary , Brown, Robert H. , Brady, Scott T.

Dying-back degeneration of motor neuron axons represents an established feature of familial amyotrophic lateral sclerosis (FALS) associated with superoxide dismutase 1 (SOD1) mutations, but axon-autonomous effects of pathogenic SOD1 remained undefined. Characteristics of motor neurons affected in FALS include abnormal kinase activation, aberrant neurofilament phosphorylation, and fast axonal transport (FAT) deficits, but functional relationships among these pathogenic events were unclear. Experiments in isolated squid axoplasm reveal that FALS-related SOD1 mutant polypeptides inhibit FAT through a mechanism involving a p38 mitogen activated protein kinase pathway. Mutant SOD1 activated neuronal p38 in mouse spinal cord, neuroblastoma cells and squid axoplasm. Active p38 MAP kinase phosphorylated kinesin-1, and this phosphorylation event inhibited kinesin-1. Finally, vesicle motility assays revealed previously unrecognized, isoform-specific effects of p38 on FAT. Axon-autonomous activation of the p38 pathway represents a novel gain of toxic function for FALS-linked SOD1 proteins consistent with the dying-back pattern of neurodegeneration characteristic of ALS.

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