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Erin Chown 2016.12.05 APBDRF Scientific Advisory Board Meeting
Identification of therapeutic targets in an APBD mouse model Erin Chown APBDRF Scientific Advisory Board Meeting
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Adult Polyglucosan Body Disease (APBD)
Autosomal recessive mutations in glycogen branching enzyme (GBE1) Massa et al. 2008 Massa et al. 2008 Lossos et al. 1981 Vos et al. 1983
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Glycogen synthesis UDP UDP GYG Glycogenin GYG
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Glycogen synthesis Glycogenin Glycogen synthase GYG GYG GYS1 GYG GYS1
UDP UDP GYG GYG GYS1 UDP UDP Glycogenin Glycogen synthase GYG GYS1
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Glycogen synthesis Glycogenin Glycogen synthase
UDP UDP GYG GYG GYS1 UDP UDP PTG Glycogenin Glycogen synthase Protein targeting to glycogen GYG GYS1 PTG
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Glycogen synthesis Glycogenin Glycogen synthase
UDP UDP GBE1 GYG GYG GYG GYS1 UDP UDP PTG Glycogenin Glycogen synthase Protein targeting to glycogen Glycogen branching enzyme GYG GYS1 PTG GBE1
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Glycogen synthesis Glycogenin Glycogen synthase
UDP UDP GYG GBE1 GBE1 GYG GYG GYG GYS1 GYS1 UDP UDP PTG Glycogenin Glycogen synthase Protein targeting to glycogen Glycogen branching enzyme GYG GYS1 PTG GBE1
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APBD Polyglucosan body Glycogenin Glycogen synthase
UDP UDP GYG Polyglucosan body GBE1 GBE1 GYG GYG GYG GYS1 GYS1 UDP UDP PTG Glycogenin Glycogen synthase Protein targeting to glycogen Glycogen branching enzyme GYG GYS1 PTG GBE1
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Therapeutic targets: GYS1 & PTG
UDP UDP GBE1 GBE1 GYG GYG GYG GYG GYS1 GYS1 UDP UDP PTG Reduce total glycogen produced Increase branch frequency
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Aim: Identify therapeutic targets Characterize the effect of Gys1 or Ptg deficiency in an APBD mouse model
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Gys1 & Ptg knockout in the APBD mouse model
Gbe1ys/ys mouse model: p.Y329S mutation (Akman et al. 2015) 6 mo. 12 mo.
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Gys1 & Ptg knockout in the APBD mouse model
Dr. Bart Pederson Gbe1ys/ys mouse model: p.Y329S mutation Interrogation of potential therapeutic targets: (Akman et al. 2015) Gys1 Ptg Wild-type mouse WT APBD model Gbe1ys/ys Mono-allelic knockout Gbe1ys/ys Gys1+/- Gbe1ys/ys Ptg+/- Full knockout Embryonic lethal Gbe1ys/ys Ptg-/- Control mice Gys1+/- Ptg-/- 6 mo. Physiology & Longevity Behavioural Histological Biochemical 12 mo.
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Gys1 & Ptg knockout in the APBD mouse model
Dr. Bart Pederson Gbe1ys/ys mouse model: p.Y329S mutation Interrogation of potential therapeutic targets: (Akman et al. 2015) Gys1 Ptg Wild-type mouse WT APBD model Gbe1ys/ys Mono-allelic knockout Gbe1ys/ys Gys1+/- Gbe1ys/ys Ptg+/- Full knockout Embryonic lethal Gbe1ys/ys Ptg-/- Control mice Gys1+/- Ptg-/- 6 mo. Physiology & Longevity Behavioural Histological Biochemical 12 mo.
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APBD mouse model (Gbe1ys/ys) rescues:
Gys1 knockdown in the APBD mouse model (Gbe1ys/ys) rescues: Disease progression-associated decline in body mass Reduced lifespan
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Gys1 knockdown in the Gbe1ys/ys mouse rescues:
Gait abnormality
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Gys1 knockdown in the Gbe1ys/ys mouse rescues:
Gait abnormality Balance beam Activity level
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WT Gbe1ys/ys Gbe1ys/ys Gys1+/- Gys1+/- PASD GFAP IBA1
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Gys1 deficiency reduces PB and glycogen accumulation
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Gys1 deficiency reduces PB accumulation in skeletal muscle and heart
WT Gbe1ys/ys Gbe1ys/ys Gys1+/- Gys1+/- Muscle Heart
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Gys1 deficiency reduces PB and glycogen accumulation
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Gys1 & Ptg knockout in the APBD mouse model
Dr. Bart Pederson Gbe1ys/ys mouse model: p.Y329S mutation Interrogation of potential therapeutic targets: (Akman et al. 2015) Gys1 Ptg Wild-type mouse WT APBD model Gbe1ys/ys Mono-allelic knockout Gbe1ys/ys Gys1+/- Gbe1ys/ys Ptg+/- Full knockout Embryonic lethal Gbe1ys/ys Ptg-/- Control mice Gys1+/- Ptg-/- 6 mo. Physiology & Longevity Behavioural Histological Biochemical 12 mo.
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Ptg deficiency improves
Gbe1ys/ys lifespan and kyphosis phenotype Gbe1ys/ys Gbe1ys/ys Ptg-/-
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Ptg deficiency rescues
body mass decline and a measure of motor function Gbe1ys/ys Gbe1ys/ys Ptg-/-
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…and Ptg knockout rescues Gbe1ys/ys mouse hind limb gait abnormalities
Mouse image adapted from TreadScan
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…and Ptg knockout rescues Gbe1ys/ys mouse hind limb gait abnormalities
Mouse image adapted from TreadScan
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Gbe1ys/ys Ptg+/- Gbe1ys/ys Ptg-/- WT Gbe1ys/ys Ptg-/- PASD GFAP IBA1
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Ptg deficiency reduces PB and glycogen accumulation
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Ptg deficiency reduces PB accumulation in skeletal muscle and heart
Gbe1ys/ys Ptg+/- Gbe1ys/ys Ptg-/- WT Gbe1ys/ys Ptg-/- Muscle Heart
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Ptg deficiency reduces PB and glycogen accumulation
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Gys1 is a more effective target
Conclusions Gys1 or Ptg are both effective therapeutic targets for APBD resulting in improvements in: Body mass, kyphosis and longevity Motor deficits PB and glycogen accumulation Indicators of neurodegeneration Gys1 is a more effective target
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Acknowledgements Dr. Berge Minassian & Lab: Ami Perri
Dr. Julie Turnbull Dr. Peixiang Wang Yunlin Xue Xiaochu Zhao Dr. Bart Pederson & Lab Dr. Orhan Akman
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