Note that the obliteration of either NF-??B next activation or Hes1 activity was followed by neuron death. The addition of TGF??1 did not reverse these effects. Click here for file(3.6M, TIFF) Acknowledgements P Chacon was supported by the Instituto de Salud Carlos III (Contratos Post-Doctorales Sara Borrell). This work was financed by the Fundaci?? La Caixa (grant BM05-184) and the Spanish Ministry of Education and Science (grants BFU2007-63033 and BFU2010-20995). We are indebted to Emmanuel Villanueva, ??ngel J del Marco and Rosa M Garc??a-Mej??as for technical assistance. We thank Dr Lisardo Bosc?? (Madrid, Spain) for providing the IKK plasmids, Dr Mayte Coyras (Madrid, Spain) for the p65/RelA plasmid, Dr Ryoichiro Kageyama (Kyoto, Japan) for the Hes1 plasmid, Dr Phil Jones (Cambridge, UK) for the Hes6 plasmid.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, uniformly fatal, neurodegenerative disease. The annual incidence of ALS is reported to be 1.5 to 2.7 per 100,000 in Western countries [1,2]. There is currently no cure for ALS, and approximately 6,500 individuals die from the disease each year in the United States, making it the most common adult-onset form of motor neuron disease, and the third most common form of neurodegeneration [3]. Median age of symptom onset is between 65 and 67 years, meaning that ALS is often considered to be a disease associated with aging [4]. An important historical fact is that Jean Martin Charcot first defined ALS as a pure motor neuron disease [5].

Since then, the traditional view has been that cognition remains intact in the majority of ALS patients except for a small proportion who developed florid dementia (approximately 5% of cases). This view has only relatively recently been challenged and the current consensus is that ALS and frontotemporal lobar degeneration (FTLD) form part of a continuum of neurological disease: patients with familial and sporadic ALS exhibit signs of frontal lobe degeneration, including language dysfunction, changes in personality and executive function with relative sparing of memory [6-9]. Similarly, FTLD is complicated by motor neuron dysfunction in a significant proportion of patients. These observations directly led to diagnostic criteria categorizing cognitive and behavioral dysfunction in ALS [10].

The concept that ALS and FTLD represent a continuum of disease was further supported by neuropathological evidence concerning Anacetrapib the abnormal protein aggregates observed in degenerating neurons. Initially, immunoreactive, ubiquitin-positive neuronal inclusions were identified in ALS and FTLD selleckchem U0126 and provided a first clue of a shared pathogenic mechanism between these conditions. Then, in 2006, the TAR DNA-binding protein 43 kDa (TDP-43) was discovered to be the main component of the ubiquinated inclusions [11].