title: Drosophila Clock Is Required in Brain Pacemaker Neurons to Prevent Premature Locomotor Aging Independently of Its Circadian Function.
abstract: Circadian clocks control many self-sustained rhythms in physiology and behavior with approximately 24-hour periodicity. In many organisms, oxidative stress and aging negatively impact the circadian system and sleep. Conversely, loss of the clock decreases resistance to oxidative stress, and may reduce lifespan and speed up brain aging and neurodegeneration. Here we examined the effects of clock disruptions on locomotor aging and longevity in Drosophila. We found that lifespan was similarly reduced in three arrhythmic mutants (ClkAR, cyc0 and tim0) and in wild-type flies under constant light, which stops the clock. In contrast, ClkAR mutants showed significantly faster age-related locomotor deficits (as monitored by startle-induced climbing) than cyc0 and tim0, or than control flies under constant light. Reactive oxygen species accumulated more with age in ClkAR mutant brains, but this did not appear to contribute to the accelerated locomotor decline of the mutant. Clk, but not Cyc, inactivation by RNA interference in the pigment-dispersing factor (PDF)-expressing central pacemaker neurons led to similar loss of climbing performance as ClkAR. Conversely, restoring Clk function in these cells was sufficient to rescue the ClkAR locomotor phenotype, independently of behavioral rhythmicity. Accelerated locomotor decline of the ClkAR mutant required expression of the PDF receptor and correlated to an apparent loss of dopaminergic neurons in the posterior protocerebral lateral 1 (PPL1) clusters. This neuronal loss was rescued when the ClkAR mutation was placed in an apoptosis-deficient background. Impairing dopamine synthesis in a single pair of PPL1 neurons that innervate the mushroom bodies accelerated locomotor decline in otherwise wild-type flies. Our results therefore reveal a novel circadian-independent requirement for Clk in brain circadian neurons to maintain a subset of dopaminergic cells and avoid premature locomotor aging in Drosophila.
authors.affiliation: Genes Circuits Rhythms and Neuropathology, Brain Plasticity Unit, ESPCI Paris/CNRS, PSL Research University, Paris, France.
authors.forename: Alexandra
authors.identifier: http://orcid.org/0000-0002-3183-7343
authors.initials: A
authors.lastname: Vaccaro
authors.affiliation: Genes Circuits Rhythms and Neuropathology, Brain Plasticity Unit, ESPCI Paris/CNRS, PSL Research University, Paris, France.
authors.forename: Abdul-Raouf
authors.initials: AR
authors.lastname: Issa
authors.affiliation: Integrated Physiology of the Brain Arousal Systems (WAKING), Lyon Neuroscience Research Centre, INSERM/CNRS/UCBL1, Lyon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Seugnet
authors.affiliation: Genes Circuits Rhythms and Neuropathology, Brain Plasticity Unit, ESPCI Paris/CNRS, PSL Research University, Paris, France.
authors.forename: Serge
authors.identifier: http://orcid.org/0000-0002-4278-454X
authors.initials: S
authors.lastname: Birman
authors.affiliation: Genes Circuits Rhythms and Neuropathology, Brain Plasticity Unit, ESPCI Paris/CNRS, PSL Research University, Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Klarsfeld
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000375:Aging / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D056926:CLOCK Proteins / Q000235:genetics* / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D004330:Drosophila / Q000235:genetics* / Q000254:growth & development; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D008124:Locomotion / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; C120526:Clk protein, Drosophila; D029721:Drosophila Proteins; C507073:PDFR protein, Drosophila; D043562:Receptors, G-Protein-Coupled; C112805:cyc protein, Drosophila; C096445:tim protein, Drosophila; D056926:CLOCK Proteins