Lecture 14: Genetics of sleep disorders Flashcards

Question

stuff to do with PER2?

Answer 1

PER2 has many phosphorylation sites (21 in total) with different roles. PER2 has different actions depending where it is phosphorylated. some increase speed of nuclear translocation (PER1 moving into the nucleus). some increase ability of PERCRY to inhibit BMAL/CLOCK. others increase PER degredation. Gallego and Virshup 2007, Nature Reviews Molecular Cell Biology

Answer 2

FASPS mutation reduces ‘FASPS site’ phosphorylation but increases per degradation. cyclohexamide blocks protein synthesis, so can masure degredation rate. PER2 degrades faster if FASPS mimic added. phosphorylated mimic of PER2 degrades very slowly. can look at late stage when degraded and compare wt to FASPS. cells not expressing CK1 have no difference in PER2 expression. If add CK1ε FASPS has decreased PER2 so degradation has increased. Dead CK1ε has no effect. therefore FASPS enhances the ability of CK1 enzyme to degrade PER2.

Answer 3

two pathways which control the fate of PER2 protein. β-TrCP site has instant degredation. phosphorylated by CK1d/e FASP site takes longer to degrade, phosphorylated by other kinases, but allowed CK1d/e to target other sites further down the pathway. FASPS mutation can't phosphorylate the FASP pathway, so uses the faster β-TrCP pathway and accelerates the clock.

Answer 4

Extreme late chronotype - Sleep onset insomnia, inability to wake up at a conventional time Up 16% of late adolescents. no single mutation like FASPS in humans. PER3 4/4 increases chances. Mis-sense mutation (V647G) in Per3 increases risk of developing DSPS. Mutation in CK1ε (S408N) gene decreases risk of developing DSPS. Point mutations that dramatically lengthen period have been identified in mice ``` Afterhours (C358S) and overtime (I364T) mutations in FBXL3 -clock period >26hr -block binding to CRY and subsequent targeting for degradation ``` THIS FOR MICE THO THIS BIT, MAYBE HOOMANS TOO WHO KNOWS

Answer 5

GENE HUMAN SLEEP PHENOTYPE Per1 Advanced sleep phase Per2 Advance sleep phase Per3 Advance sleep phase (long per3 allele) Delayed sleep phase (short per3 allele) CK1 delta Advanced sleep phase CK1 epsilon Advanced sleep phase Clock Delayed sleep phase and hyposomnia (3111C allele) (disputed) ``` GENE PREDICTED HUMAN SLEEP PHENOTYPE Cry1 Advanced sleep phase Cry2 Delayed sleep phase Altered NREM bout duration and EEG activity FBXL3 Delayed sleep phase Bmal1 Irregular sleep timing ```

Answer 6

1. Using light: Regardless of condition (ASPS/DSPS/jet-lag etc.) approach should be: Up to 2h after desired wake-up time: maximise activation of melanopsin (while making colour resemble daylight i.e. white) At least 2h before desired sleep time: minimise activation of melanopsin (while making colour resemble ‘night’ i.e. bluer) 2. Melatonin: Used alone or in combination with light for many sleep and circadian-related disorders. e.g. melatonin agonist (Tasimelteon) In totally blind patients with non 24-h sleep syndrome. 3. Direct pharmacological targeting of the clock: reveb ligands, CK1 inhibitors, CRY activators. check papers etc. LiCl used clinically for treatment of bipolar disorder – lengthens period!