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bioRxiv · 10.1101/370924

Neuronal overexpression of DYRK1A/minibrain alters motor decline, neurodegeneration and synaptic plasticity in Drosophila

Lowe, S.·Usowicz, M.·Hodge, J. J.
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Abstract

Down syndrome (DS) is characterised by abnormal cognitive and motor development, and later in life by progressive Alzheimers disease (AD)-like dementia, neuropathology, declining motor function and shorter life expectancy. It is caused by trisomy of chromosome 21 (Hsa21), but how individual Hsa21 genes contribute to various aspects of the disorder is incompletely understood. Previous work has demonstrated a role for triplication of the Hsa21 gene DYRK1A in cognitive and motor deficits, as well as in altered neurogenesis and neurofibrillary degeneration in the DS brain, but its contribution to other DS phenotypes is unclear. Here we demonstrate that overexpression of minibrain (mnb), the Drosophila ortholog of DYRK1A, in the Drosophila nervous system accelerated age-dependent decline in motor performance and shortened lifespan. Overexpression of mnb in the eye was neurotoxic and overexpression in ellipsoid body neurons in the brain caused age-dependent neurodegeneration. At the larval neuromuscular junction, an established model for mammalian central glutamatergic synapses, neuronal mnb overexpression enhanced spontaneous vesicular transmitter release. It also slowed recovery from short-term depression of evoked transmitter release induced by high-frequency nerve stimulation and increased the number of boutons in one of the two glutamatergic motor neurons innervating the muscle. These results provide further insight into the roles of DYRK1A triplication in abnormal aging and synaptic dysfunction in DS.\n\nAuthor summaryDown syndrome (DS) is caused by three copies of chromosome 21 instead of the usual two. It is characterised by cognitive and motor deficits, which worsen with age resulting in Alzheimers disease (AD). Which genes on chromosome 21 cause these phenotypes is incompletely understood. Here we demonstrate that neuronal overexpression of minibrain, the Drosophila ortholog of the chromosome 21 gene DYRK1A, causes age-dependent degeneration of brain neurons, accelerates age-dependent decline in motor performance and shortens lifespan. It also modifies presynaptic structure, enhances spontaneous transmitter release and slows recovery from short-term depression of synaptic transmission at a model glutamatergic synapse. These findings give insight into the role of DYRK1A overexpression in aberrant aging and altered information processing in DS and AD.

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Lowe, S., Usowicz, M., Hodge, J. J.. 2018-07-17. Neuronal overexpression of DYRK1A/minibrain alters motor decline, neurodegeneration and synaptic plasticity in Drosophila. https://doi.org/10.1101/370924

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