**10. Conclusions**

**9. ALS and PPAR gamma**

262 Update on Amyotrophic Lateral Sclerosis

In ALS, expression of PPAR gamma (mARN and protein) has not been precisely investigated in neurons. However, the upregulation of Wnt/beta-catenin signaling observed in ALS suggests that PPAR gamma might be downregulated due to the fact that these two systems generally operate in the opposite way [1–3, 5]. Neuroinflammation is a common pathological feature in NDs, particularly in ALS. PPAR gamma may be a key regulator of neuroinflamma‐ tion. PPAR gamma inhibits NF-kappaB-mediated inflammatory signaling at multiple sites [48]. PPAR gamma might be a relevant regulator of neuroinflammation and possibly a new target for the development of therapeutic strategies for ALS. A potentially therapeutic pathway in ALS may be the activation by PPAR gamma agonists due to their ability to block neuropa‐ thological damages caused by inflammation [49]. The neuroprotective effect of pioglitazone has been demonstrated in G93A SOD1 transgenic mouse model of ALS and shows a significant increase in their survival. Pioglitazone protects motor neurons against p38-mediated neuronal death and NF-kappaB-mediated glial inflammation via a PPAR gamma-independent mecha‐ nism [50]. In ALS, PPAR gamma controls natural protective mechanisms against lipid peroxidation [51]. PPAR gamma-driven transcription selectively increases in the spinal cord of hSOD1G93A mice. This is correlated with the upregulation of lipid detoxification enzymes such as the lipoprotein lipase and glutathione S-transferase alpha-2, implied in scavenging lipid peroxidation by-products. Anticipation of protective reactions by pharmacological PPAR gamma modulation of the transcriptional activity attenuates neurodegeneration induced by lipid peroxidation. PPAR gamma activation is neuroprotective in a Drosophila model of ALS [52]. This Drosophila model of ALS based on TDP-43 recapitulates several aspects of ALS pathophysiology. Pioglitazone rescues TDP-43-dependent locomotor dysfunction in motor neurons and glia. PPAR gamma activation in neurons and glia is partially neuroprotective and restores metabolic alterations in ALS. Superoxide dismutase (SOD1)-G93A transgenic mice benefit from oral treatment with the PPAR gamma agonist pioglitazone [53]. Pioglitazonetreated transgenic mice reveal improved muscle strength and body weight, exhibit a delayed disease onset and survive significantly longer than non-treated SOD1-G93A mice. Pioglita‐ zone-induced neuroprotection of motor neurons of the spinal cord is complete at day 90. There is also preservation of the median fiber diameter of the quadriceps muscle, indicating a morphological and functional protection of motor neurons induced by pioglitazone. However, in a phase II double-blind controlled clinical trial, the PPAR gamma agonist pioglitazone in

combination with riluzole does not increase survival in ALS patients [54].

PPAR gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator that works together with the transcription factor PPAR gamma in the regulation of mitochondrial biogenesis. PGC-1alpha plays a role in several neurodegenerative pathologies [26]. PGC-1al‐ pha protects neurons and alters disease progression in a PGC-1alpha transgenic mice crossed with SOD1 mutant G93A DL mice [55]. In these mice, the progression of the disease has been shown to be significantly slower. There is also a markedly improved performance on the rotarod test associated with an improved motor activity with a decreased loss of motor neurons and less degeneration of neuromuscular junctions. By using a double transgenic mouse model where PGC-1alpha is over-expressed in a SOD1 transgenic mouse (TgSOD1-G93A/

PPAR agonists represent promising therapeutics for NDs such as multiple sclerosis, ALS and Alzheimer's disease (AD). Their activation affects many pathological mechanisms. PPAR activation can weaken or reprogram the immune response, stimulate metabolism, improve mitochondrial function, promote axon growth and induce progenitor cells to differentiate into myelinating oligodendrocytes [58]. The mechanisms of action of PPAR agonists are various and may be useful at many stages of diseases. Type, timing and dose of PPAR agonists may vary depending on injury severity, progression of disease or cellular targets such as neurons, microglia, oligodendrocytes, and may explain a number of conflicting results in several studies. PPAR gamma may be useful due to its anti-inflammatory properties. Moreover, PPAR gamma agonists induce beta-catenin inhibition [3, 5], which represents a rationale to use it when the Wnt/beta-catenin pathway is upregulated such as in Parkinson's disease, multiple sclerosis, ALS, Huntington's disease and Friedreich's ataxia [8]. However, in AD, PPAR gamma levels (mRNA and protein) have been found to be elevated in brain tissues [59, 60]. Although PPAR gamma expression is high in AD, PPAR gamma agonists have been used in AD humans and various AD animal models and have been shown to induce beneficial effects, partly due to their anti-inflammatory effects [61–67]. Even if the PPAR gamma agonist pioglitazone, in combination with riluzole, does not increase survival in ALS patients [54], PPAR gamma represents a useful therapeutic target in several animal models. Inhibition of the Wnt/betacatenin pathway might also represent a therapeutic approach in ALS animal model.
