The essential role of p53 Upregulated Modulator of Apoptosis and its regulation by FoxO3a transcription factor in {beta}-amyloid induced neuron death [Neurobiology]

February 24th, 2014 by Akhter, R., Sanphui, P., Biswas, S. C.

Neurodegeneration underlies the pathology of Alzheimer disease (AD). The molecules responsible for such neurodegeneration in AD brain are mostly unknown. Recent findings indicate that the BH3-only proteins of Bcl-2 family play an essential role in various cell death paradigms including neurodegeneration. Here we report that Puma (p53 Upregulated Modulator of Apoptosis), an important member of BH3-only proteins is upregulated in neurons upon toxic β-amyloid 1-42 (Aβ1-42) exposure in both in vitro and in vivo. Downregulation of Puma by specific siRNA provides significant protection against neuron death induced by Aβ1-42. We further demonstrate that the activation of p53 and inhibition of PI3K/Akt pathways induce Puma. The transcription factor FoxO3a which is activated when PI3K/Akt signaling is inhibited, directly binds with Puma gene and induces its expression upon exposure of neurons to oligomeric Aβ1-42. Moreover, Puma cooperates with another BH3-only protein, Bim which is already implicated in AD. Our results thus suggest that Puma is activated by both p53 and PI3K/Akt/FoxO3a pathways and cooperates with Bim to induce neuron death in response to Aβ1-42.
  • Posted in Journal of Biological Chemistry, Publications
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