Abstract

SUMMARYAltered function of Cdk5 kinase is associated with many forms of neurodegenerative disease in humans. We show here that inactivating the Drosophila Cdk5 ortholog, by mutation of its activating subunit, p35, causes adult-onset neurodegeneration in the fly. In the mutants, a vacuolar neuropathology is observed in a specific structure of the central brain, the ‘mushroom body’, which is the seat of olfactory learning and memory. Analysis of cellular phenotypes in the mutant brains reveals some phenotypes that resemble natural aging in control flies, including an increase in apoptotic and necrotic cell death, axonal fragmentation, and accumulation of autophagosomes packed with crystalline-like depositions. Other phenotypes are unique to the mutants, notably age-dependent swellings of the proximal axon of mushroom body neurons. Many of these phenotypes are also characteristic of mammalian neurodegenerative disease, suggesting a close relationship between the mechanisms of Cdk5-associated neurodegeneration in fly and human. Together, these results identify the cellular processes that are unleashed in the absence of Cdk5 to initiate the neurodegenerative program, and they provide a model that can be used to determine what part each process plays in the progression to ultimate degeneration.

Highlights

  • Progression of neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), leads to brain atrophy with neuronal loss

  • Cdk5 is one of the major kinases that hyperphosphorylates tau to create the forms present in the neurofibrillary tangles that are characteristic of AD and other neurodegenerative diseases, and Cdk5 hyperphosphorylates neurofilament to produce forms that are mislocalized to the cell soma in motor neuron disease

  • We show that aging p35 mutant flies suffer adult-onset neurodegeneration, with overt tissue disruption in a specific structure of the central brain, the ‘mushroom bodies’ (MB), which are the seat of olfactory learning and memory

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Summary

Introduction

Progression of neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), leads to brain atrophy with neuronal loss. These diseases are associated with a complex array of cellular and molecular pathologies. One of the key issues in neurodegenerative disease is to understand the relationships among this array of phenotypes: which ones initiate the disease and which are late manifestations of neuronal dysfunction? Cdk is one of the major kinases that hyperphosphorylates tau to create the forms present in the neurofibrillary tangles that are characteristic of AD and other neurodegenerative diseases, and Cdk hyperphosphorylates neurofilament to produce forms that are mislocalized to the cell soma in motor neuron disease

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