Case Study 3: Werner’s Syndrome a progeriac disease Cell Division Cell Cycle Aging What mechanisms control the proliferation of cells? What governs the life span of an organism? Cell death as a necessary and important part of development: Apoptosis (programmed cell death, pcd)

Context: George Martin, 1978 ‘Genetic Syndromes in Man with Potential Relevance to the Pathology of Aging’ < 7000 genes: involved in degenerative processes associated with aging Between 70 and 7 genes: control processes having large impact on senescence What is cell senescence? Divide certain # of times then enter G 0 and eventually die

Aging a multigene process 10 genetic diseases that mimic aging process—but only in part Chromosomal aneuploides  Down’s syndrome Known single mutant gene  Werner’s syndrome Known single gene  Hutchinson-Gilford’s Progeria Dementia, cataracts, diabetes, hair graying, cancer Skin ‘thinning’, Hair graying and loss, atherosclerosis, Cataracts, cancer diabetes, osteoporosis Autosomal recessive Skin ‘thinning’ hair loss, atherosclerosis, osteoporosis, Hypertension Autosomal dominant Birth In 20’s Helicase Birth/1yr Lamin A (LMNA Gene) Appears

Werner’s Syndrome

Werner’s history Named for C. W. Otto Werner ( ) Rural doctor, medical officer in German Navy WWI Rare autosomal recessive disease Approx 1 in 200 people carriers for defective gene Approx 3 in 1,000,000 people have the disease (Slightly higher percentage in Japan) Onset of symptoms early to mid 20’s, Major cause of death—heart attack in mid 40s

Cells of Progeria and WS Cell Culture What do cells need to proliferate? Progeriac Fibroblasts: Rarely ever double Few cell generations before death When compare fibroblasts of child with Progeria and their parent Child’s cells are ‘older’ in terms of replication Fibroblasts ‘normal cells’ divide ~12 to 24 hours Divide approx 50times in culture Note: Often ‘Progeriac’ used to describe any premature aging as well as the specific disorder Hutchinson Gilford Progeria

Why do we age?/How how do we age? Short answer: Don’t know 3 Hypotheses for Aging: The 3 R’s: Mutation effecting DNA reading, replicating or repair 1) Free Radical Theory: Aging due to accumulation of damage from free radicals 3) Helicase defect: Mutation Chromosome 8 in WRN gene all 35 known mutations result in truncated protein all ‘remove’ nuclear targeting sequence different mut’s associated with different cancers 2) Telomere Theory: Chromosome ends shorten with divisions Cause of Werner’s syndrome

Case Study Focuses Cell Cycle and its regulation Telomeres and replication Cell death: damage and apoptosis