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Removing toxic aggregates that our cells cant break down

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Removing toxic aggregates that our cells can't break down ... Janet Sparrow: ophthalmotoxic junk. Ana Maria Cuervo: gene engineering for lysosomal targeting ... – PowerPoint PPT presentation

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Title: Removing toxic aggregates that our cells cant break down


1
Removing toxic aggregates that our cells cant
break down Aubrey de Grey Department of
Genetics, University of Cambridge Email
ag24_at_gen.cam.ac.uk Website http//www.gen.cam.ac.
uk/sens/
2
The lysosome the cells garbage disposal
machinery of last resort
Amino acids
P
Lyso-some
R
?
M
3
The problem the lysosome is not
omnipotent Livers solution exocytosis
Lyso-some
Lyso-some
Not done elsewhere kidneys would suffer?
4
All other cells solution sequestration Obvious
ly fails eventually Cellular function
impaired Cell becomes toxic Cell dies
5
  • Lysosomal junk
  • The four major types
  • Lipofuscin. Universal marker of postmitotic cell
    aging reaches 10 of total cell mass in heart
    and motor neurons. No clear proof of
    pathogenesis, but in vitro evidence is strong

6
  • Lysosomal junk
  • The four major types
  • 2) A2E -- weird molecule created by reaction of
    the membrane lipid phosphatidylethanolamine with
    the photoreceptor pigment retinal. More or less
    proven to be pathogenic causes age-related
    macular degeneration.

7
  • Lysosomal junk
  • The four major types
  • 3) Hyperphosphorylated tau in neurons. Widely
    believed to be a major cause of Alzheimers
    disease. Similar aggregates form in other
    neurodegenerative diseases and normal aging.

8
  • Lysosomal junk
  • The four major types
  • 4) Oxidised (etc) cholesterol and cholesteryl
    esters (oxysterols) in arterial macrophages.
    Causes them to become foam cells, then fatty
    streaks, and eventually atherosclerotic plaques.

9
  • Why dont graveyards fluoresce?
  • de Grey 2002, Trends in Biotechnology 20452-455
  • These (often fluorescent) materials do not
    accumulate in nature, even in areas rich in the
    remains of animals that produce them. Thus,
    something degrades them. They are energy-rich,
    so micro-organisms could live off them.
  • Bacterial strains exist with astonishingly varied
    catabolic activities, and are being used by many
    groups for bioremediation purposes. They degrade
    rubber, TNT, PCBs, dioxin, ... Some fungi are
    similarly versatile.
  • Can micro-organisms capable of degrading
    lysosomal junk be isolated from the soil???

10
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11
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12
  • Some FAQs
  • Q Arent foam cell lysosomes mainly native
    cholesterol?
  • A Yes - the major lysosomal component is not
    necessarily the culprit - the culprit may impair
    lysosomal trafficking of normally benign things
  • Q Wont we need an awful lot of different
    enzymes?
  • A Probably not - degradation is synergistic -
    one step will often form a substrate for an
    enzyme we already have
  • Q What about immune rejection?
  • A Same problem/solutions as for normal gene
    therapy

13
  • Steps to biomedical application
  • Isolate competent strains select by starvation
  • Identify the enzymes (mutagenesis, chemistry,
    genomics)
  • Make lysosome-targeted transgenes, assay cell
    toxicity
  • Assay competence in vitro (more
    mutagenesis/selection)
  • Construct transgenic mice, assay toxicity in vivo
  • Assay competence in disease models (apoE-/- mice,
    etc.)
  • Test in humans as for lysosomal storage diseases

14
Funding the story so far 2001, 2002 Kronos deem
it too sciencey -( 2003 Archer wows NIA
officials at IABG10 -) 2004 SENS 5 (July
26th, NIA offices, Bethesda) Jay Jerome
atherogenic junk Ralph Nixon neurotoxic
junk Janet Sparrow ophthalmotoxic junk Ana Maria
Cuervo gene engineering for lysosomal
targeting Roscoe Brady protein engineering for
lysosomal targeting Bruce Rittmann, Perry
McCarty, Pedro Alvarez biorem. Fingers crossed.
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