A potential new role for the transcriptional co-activator PGC-1α during neurodegeneration: a protector turning foe?

Thursday, October 11, 2012 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center, Building 45	NINDS	OXIDSTRESS-4

Author

• MH Schubert

Abstract

The transcriptional co-activator PGC-1α performs regulatory functions in mitochondrial oxidative phosphorylation (Wu et al., 1999) and in protection against reactive oxygen species (ROS) (St-Pierre et al., 2006). The absence of functional PGC-1α protein accelerates neurodegenerative diseases such as Parkinson’s (Pacelli et al., 2011; Shin et al., 2011), Huntington’s (Cui et al., 2006), Alzheimer’s (Qin et al., 2009) disease and amyotrophic lateral sclerosis (Liang et al., 2011). In contrast, Ciron et al., 2012, reported that, while AAV-vector-encoded PGC-1α-overexpression increased neuronal respiration, prolonged PGC-1α-expression caused mitochondrial depolarization, inhibited retrograde transport within the nigrostriatal system and selectively killed dopaminergic neurons in vivo. The retraction and disconnection of neural processes occurs during most neurodegenerative diseases. We hypothesized that PGC-1α-overexpression, besides balancing energy metabolism and ROS-protection, may cause cytoskeleton-destabilization and impair intracellular transport, subsequently affecting energy metabolism and cell viability. We investigated lentiviral vector-encoded PGC-1α-overexpression in human neural progenitor cells and found that PGC-1α 1) arrested cell proliferation, 2) retracted cellular processes, 3) destabilized the cytoskeleton (microtubules), 4) selectively increased β-tubulin-III expression, 5) without causing immediate mitochondrial depolarization. These results suggest a potential new mechanism for neural cell degeneration and/or adaptation, providing a rationale for multi-level transcriptional and posttranslational controls of PGC-1α.

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