NRF2 as a therapeutic opportunity to impact in the molecular roadmap of ALS.

Amyotrophic Lateral Sclerosis (ALS) is a devastating heterogeneous disease with still no convincing therapy. To identify the most strategically significant hallmarks for therapeutic intervention, we have performed a comprehensive transcriptomics analysis of dysregulated pathways, comparing datasets from ALS patients and healthy donors. We have identified crucial alterations in RNA metabolism, intracellular transport, vascular system, redox homeostasis, proteostasis and inflammatory responses. Interestingly, the transcription factor NRF2 (nuclear factor (erythroid-derived 2)-like 2) has significant effects in modulating these pathways. NRF2 has been classically considered as the master regulator of the antioxidant cellular response, although it is currently considered as a key component of the transduction machinery to maintain coordinated control of protein quality, inflammation, and redox homeostasis. Herein, we will summarize the data from NRF2 activators in ALS pre-clinical models as well as those that are being studied in clinical trials. As we will discuss, NRF2 is a promising target to build a coordinated transcriptional response to motor neuron injury, highlighting its therapeutic potential to combat ALS.

Dysfunction of the PI3K-Akt-GSK-3 pathway is a common feature in cell culture and in vivo models of prion disease.

AIMS: Transmissible spongiform encephalopathies, also called prion diseases, are characterized by the cerebral accumulation of misfolded prion protein (PrP(SC) ) and subsequent neurodegeneration. However, despite considerable research effort, the molecular mechanisms underlying prion-induced neurodegeneration are poorly understood. Here, we explore the hypothesis that prions induce dysfunction of the PI3K/Akt/GSK-3 signalling pathway. METHODS: We employed two parallel approaches. Using cell cultures derived from mouse primary neurones and from a human neuronal cell line, we identified common elements that were modified by the neurotoxic fragment of PrP(106-126) . These studies were then complemented by comparative analyses in a mouse model of prion infection. RESULTS: The presence of a polymerized fragment of the prion protein (PrP(106-126) ) or of a prion strain altered PI3K-mediated signalling, as evidenced by Akt inhibition and GSK-3 activation. PI3K activation by the addition of insulin or the expression of a constitutively active Akt mutant restored normal levels of Akt and GSK-3 activity. These changes were correlated with a reduction in caspase activity and an increase in neuronal survival. Moreover, we found that activation of caspase 3, Erk and GSK-3 are common features of PrP(106-126) -mediated neurotoxicity in cellular systems and prion infection in the mouse cerebellum, while activation of caspase 12 and JNK was observed in cellular models. CONCLUSIONS: Our findings in cell culture and in vivo models of prion disease demonstrate marked alterations to the PI3K/Akt/GSK-3 pathway and suggest that two additional pathways contribute to PrP-induced neurotoxicity as responsible of JNK and caspase 12 activation.

Fibroblast growth factor-1 within the ventral tegmental area participates in motor sensitizing effects of morphine.

Drug addiction is viewed as a form of neural plasticity, and neurotrophic factors have been implicated in many forms of plasticity in the adult nervous system. Here we show that the fibroblast growth factor-1 (FGF-1), that is expressed on dopamine and GABA neurons of the ventral tegmental area (VTA), is involved in the sensitizing effects of morphine. The receptor FGFR-1 is expressed on VTA astrocytes, as well as dopamine and GABA neurons. FGF-1 or anti-FGF-1 infusions into the VTA during the induction (not expression) phase of sensitization advanced or blocked morphine's activating motor effects respectively, in a dose-dependent manner. Infusions into the adjacent substantia nigra, whose neurons also express FGF-1 and FGFR-1, did not modify normal morphine-induced sensitization. Biochemical traits related to morphine's sensitizing effects were altered by intra-VTA anti-FGF-1 because morphine-induced upregulation of both tyrosine hydroxylase (TH) and N-methyl d-aspartate glutamate receptor 1 (NMDAR1) in the VTA was blocked after anti-FGF-1. Changes in the activation state of VTA calcium/calmodulin-dependent kinase type II seem to participate in FGF-1-induced effects as well. We conclude that the FGF-1 system of the ventral tegmental area is required for biochemical and behavioral sensitization to this drug.