ABSTRACT
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease and studies in vitro show that motoneuron degeneration is triggered by non-cell-autonomous mechanisms. However, whether soluble toxic factor(s) released by mutant superoxide dismutase 1 (SOD1) expressing astrocytes induces death of motoneurons and leads to motor dysfunction in vivo is not known. To directly test this, healthy adult rats were treated with conditioned media derived from primary mouse astrocytes (ACM) that express human (h) SOD1G93A (ACM-hG93A) via chronic osmotic pump infusion in the lumbar spinal cord. Controls included ACM derived from transgenic mice expressing hSOD1WT (ACM-hWT) or non-transgenic mouse SOD1WT (ACM-WT) astrocytes. Rats chronically infused with ACM-hG93A started to develop motor dysfunction at 8 days, as measured by rotarod performance. Additionally, immunohistochemical analyses at day 16 revealed reactive astrogliosis and significant loss of motoneurons in the ventral horn of the infused region. Controls did not show significant motor behavior alterations or neuronal damage. Thus, we demonstrate that factors released in vitro from astrocytes derived from ALS mice cause spinal motoneuron death and consequent neuromuscular dysfunction in vivo.
Subject(s)
Amyotrophic Lateral Sclerosis/enzymology , Astrocytes/enzymology , Culture Media, Conditioned/metabolism , Motor Activity , Motor Neurons/metabolism , Spinal Nerves/metabolism , Superoxide Dismutase-1/metabolism , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/pathology , Amyotrophic Lateral Sclerosis/physiopathology , Animals , Behavior, Animal , Cell Death , Cells, Cultured , Disease Models, Animal , Gliosis , Humans , Male , Mice, Transgenic , Motor Neurons/pathology , Mutation , Primary Cell Culture , Rats, Wistar , Rotarod Performance Test , Spinal Nerves/pathology , Superoxide Dismutase-1/genetics , Time FactorsABSTRACT
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by the progressive loss of motor neurons. The cause of this selective neuronal death is unknown, but transcriptional dysregulation is recently emerging as an important factor. The physical substrate for the regulation of the transcriptional process is chromatin, a complex assembly of histones and DNA. Histones are subject to several post-translational modifications, like acetylation, that are a component of the transcriptional regulation process. Histone acetylation and deacetylation is performed by a group of enzymes (histone acetyltransferases (HATs) and deacetylases, respectively) whose modulation can alter the transcriptional state of many regions of the genome, and thus may be an important target in diseases that share this pathogenic process, as is the case for ALS. This review will discuss the present evidence of transcriptional dysregulation in ALS, the role of histone deacetylases (HDACs) in disease pathogenesis, and the novel pharmacologic strategies that are being comprehensively studied to prevent motor neuron death, with focus on sirtuins (SIRT) and their effectors.
