Reduced mRNA and protein expression of the transcriptional co-activator PGC-1alpha in post-mortem tissue of ALS patients and in the G93A transgenic ALS mouse model

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disorder with an average survival of 3–5 years after the onset of symptoms. It is characterized by a rapidly progressive paralysis due to the degeneration of motor neurons in primary motor cortex, brain stem and spinal cord. About 90% of cases occur sporadically and 10% are familial. Among the familial cases, 10–20% can be attributed to point mutations in the gene coding for the antioxidant enzyme Cu/Zn superoxide dismutase (SOD1) (Rosen et al., 1993). This discovery led to the generation of mouse models overexpressing common human SOD1 mutations (Gurney et al., 1994). The precise molecular mechanisms leading to motor neuron death have not been fully elucidated, there is, however, ample evidence that oxidative damage by reactive oxygen species (ROS) plays an important role. Mitochondria are the major source of cellular ROS production, which further increases if mitochondria are damaged (Beal, 2005, Hervias et al., 2006). The transcriptional co-activator peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC-1alpha) plays a pivotal role in the regulation of mitochondrial metabolism and biogenesis via activation of transcription factors such as nuclear respiratory factor-1 (NRF-1) (Scarpulla, 2006). Alterations in PGC-1alpha expression and function have previously been described in models of Huntington's and Alzheimer's disease (Weydt et al., 2006, Shi and Gibson, 2007).

In the present study, we investigated the mRNA and protein expression of PGC-1alpha and NRF-1 in human post mortem tissue of ALS patients as well as in the G93A-ALS mouse model in presymptomatic, early -and late symptomatic stages. We detected a reduction of PGC-1alpha and NRF-1at the mRNA and protein level, in the animal model already detectable before symptom onset. We therefore conclude that PGC-1alpha could represent an interesting therapeutic target in ALS.