Hardingham, Giles

Wyllie, David

Puddifoot, Clare Anne

Biotechnology and Biological Sciences Research Council (BBSRC)

2013-10-28T11:21:57Z

2013-10-28T11:21:57Z

2013-06-29

The transcriptional coactivator PPARgamma coactivator 1alpha (PGC-1α) is a regulator of mitochondrial biogenesis and function and is decreased in the striatum of patients with Huntington’s Disease (HD). HD is an autosomal dominant neurological disorder caused by a polyglutamine repeat in the huntingtin protein which leads to degeneration of striatal and cortical tissues. PGC-1α undergoes targeted downregulation by mutant huntingtin protein (mtHtt) and PGC-1α knockout mice have striatal lesions similar to HD transgenic mice. Exogenous PGC-1α partially reverses the toxic effects of mutant huntingtin in cultured striatal neurons while in vivo administration of PGC-1α to the striatum in a mouse model of HD reduces neuronal volume loss. Synaptic N-methyl-D-aspartate receptor (NMDAR)- activity can drive the expression of PGC-1α which is neuroprotective against oxidative and excitotoxic stress in vitro whereas extrasynaptic NMDAR expression is increased in HD. Excessive NMDAR activity, specifically through extrasynaptic rather than synaptic NMDARs, leads to excitotoxic death in neurons and its regulation has been targeted in the search for therapeutic interventions for multiple neurological disorders. The data presented in this thesis show that the repression of PGC-1α by mtHtt may be significant in the dysregulation of NMDARs in HD. Both PGC-1α knockdown and mutant huntingtin are found to increase extrasynaptic NMDAR activity and excitotoxicity in a non-additive way, suggesting common regulatory mechanisms. Furthermore exogenous PGC- 1α expression is sufficient to reverse this increase in extrasynaptic NMDAR currents and excitotoxicity by mtHtt. This thesis adds mechanistic insight into previous understanding of the synergistic roles of mtHtt, NMDAR activity and PGC-1α in HD. Finally, we show that chronic knockout of PGC-1α in the PGC-1α(-/-) mouse causes distinct alterations in glutamatergic signaling that do not mimic the observation of acute knockdown of PGC-1α. We propose that the loss of PGC-1α in a number of neurological disorders contributes to concurrent increases in aberrant glutamate signaling and excitotoxicity in these diseases.

http://hdl.handle.net/1842/8055

en

The University of Edinburgh

Léveillé F, Papadia S, Fricker M, Bell KFS, Soriano FX, Martel M-A, Puddifoot C, Habel M, Wyllie DJ, Ikonomidou C, Tolkovsky AM, Hardingham GE (2010) Suppression of the intrinsic apoptosis pathway by synaptic activity. The Journal of neuroscience : the official journal of the Society for Neuroscience 30:2623–2635

Puddifoot C, Martel M-A, Soriano FX, Camacho A, Vidal-Puig A, Wyllie DJA, Hardingham GE (2012) PGC-1 Negatively Regulates Extrasynaptic NMDAR Activity and Excitotoxicity. Journal of Neuroscience 32:6995–7000

Puddifoot CA, Chen PE, Schoepfer R, Wyllie DJA (2009) Pharmacological characterization of recombinant NR1/NR2A NMDA receptors with truncated and deleted carboxy termini expressed in Xenopus laevis oocytes. British journal of pharmacology 156:509– 518

Soriano FX, Léveillé F, Papadia S, Bell KFS, Puddifoot C, Hardingham GE (2011) Neuronal activity controls the antagonistic balance between peroxisome proliferator-activated receptor-γ coactivator-1α and silencing mediator of retinoic acid and thyroid hormone receptors in regulating antioxidant defenses. Antioxidants & redox signaling 14:1425–1436

NMDA

excitotoxicity

PGC-1α

Huntington’s Disease

Neuroprotection from the huntingtin-repressed transcriptional coactivator PGC-1α

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy