Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with progressive muscular wasting and paralysis due to loss of motor neurons in the primary motor cortex, brainstem and spinal cord. Alterations of transcriptional activity due to an unbalance of the activity of histone acetyl transferases ( HAT) and histone deacetylases (HDACs) have been described in a variety of neurodegenerative conditions in vitro and in vivo. HDACs can be grouped into four different classes with distinct cellular localization and functions. HDAC inhibitors have recently been discovered as potential neuroprotective drugs for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis ( ALS). A major limitation, however, lies in the broad spectrum of action of currently available HDAC inhibitors causing a variety of toxic side effects.

Histone deacetylases (HDACs) are important regulators of gene expression and cell differentiation. The HDAC inhibitors have recently been considered as potential novel neuroprotective drugs for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). A major limitation, however, lies in the broad spectrum of action of currently available HDAC inhibitors that may cause a variety of toxic side effects. The mRNA expression levels of the HDAC isoforms HDACs 1 to 11 have previously been characterized in rat brain but have not been studied in human tissue. Using in situ hybridization histochemistry and immunohistochemistry we assessed the distribution and expression levels of HDACs 1to 11 in postmortem ALS and control brain and spinal cord specimens (n = 6 cases each) to determine alterations in the mRNA expression pattern that could provide a basis for disease-specific therapies. We found a reduction of HDAC 11 mRNA and increased HDAC 2 levels in ALS brain and spinal cord compared with controls. A more precise knowledge of the disease-related expression pattern could lead to the development of more specific pharmacotherapeutic approaches.

We describe three patients referred to our ALS/MND clinic with suspected diagnosis of amyotrophic lateral sclerosis (ALS). The patients were all male, middle aged, and their initial symptoms were weakness and fasciculations in upper limb muscles. Results of clinical and electrophysiological examination in all cases were in accordance with possible ALS according to the revised El Escorial criteria. Other conditions mimicking ALS appeared to be excluded by extensive technical examinations and laboratory tests. Only repeated MRI examinations revealed anterior spinal cysts several years after symptom onset. This report intends to highlight this rare and difficult differential diagnosis of ALS and underlines the value of the revised El Escorial criteria in conjunction with electrophysiology to asses the certainty of the diagnosis ALS.

ALS is a fatal neurodegenerative disorder characterized by a selective loss of upper motor neurons in the motor cortex and lower motor neurons in the brain stem and spinal cord. About 10% of ALS cases are familial, in 10–20% of these, mutations in the gene coding for superoxide dismutase 1 (SOD1) can be detected. Overexpression of mutated SOD1 in mice created animal models which clinically resemble ALS. Abnormalities in glutamatergic and GABAergic neurotransmission presumably contribute to the selective motor neuron damage in ALS. By in situ hybridization histochemistry (ISH), we investigated the spinal mRNA expression of the GABAA and AMPA type glutamate receptor subunits at different disease stages on spinal cord sections of mutant SOD1 mice and control animals overexpressing wild-type SOD1 aged 40, 80, 120 days and at disease end-stage, i.e. around 140 days) (n=5, respectively). We detected a slight but statistically significant decrease of the AMPA receptor subunits GluR3 and GluR4 only in end stage disease animals.

The pathogenetic mechanisms leading to progressive neurodegeneration in amyotrophic lateral sclerosis (ALS) have not been fully elucidated. One possible factor responsible for the selective motor neuron loss in the motor cortex, brain stem and spinal cord is glutamate-induced excitotoxicity particularly mediated via α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) type glutamate receptors. Data about the expression pattern of AMPA receptors in the primary motor cortex are lacking so far. The pharmacological and physiological properties of AMPA receptors are defined by the heteromeric composition of the four different receptor subunits. Different expression patterns of these subunits at motor neurons may provide a molecular basis for increased vulnerability to excitotoxic damage. Using in situ hybridization histochemistry we did not detect any significant differences in the distribution of AMPA receptor mRNA in the motor cortex of ALS patients compared to controls.