trichostatin-a and Amyotrophic-Lateral-Sclerosis

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease characterized by degeneration of motor neuron and glial activation followed by the progressive muscle loss and paralysis. Numerous distinct therapeutic interventions have been examined but currently ALS does not have a cure or an efficacious treatment for the disorder. Glutamate- induced excitotoxicity, inflammation, mitochondrial dysfunction, oxidative stress, protein aggregation, transcription deregulation, and epigenetic modifications are associated with the pathogenesis of ALS and known to be therapeutic targets in ALS. In this review, we discuss translational pharmacological studies targeting epigenetic components to ameliorate ALS. Understanding of the epigenetic mechanisms will provide novel insights that will further identify potential biological markers and therapeutic approaches for treating ALS. A combination of treatments that modulate epigenetic components and multiple targets may prove to be the most effective therapy for ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Motor Neurons; Superoxide Dismutase; Superoxide Dismutase-1; Valproic Acid

Dynactin 1 is an axon motor protein regulating retrograde transport of various proteins and vesicles including autophagosome. We previously demonstrated that the expression levels of dynacin 1 are markedly reduced in spinal motor neurons of sporadic ALS patients. We generated a Caenorhabditis elegans model in which the expression of dnc-1, the homolog of dynactin 1, is specifically knocked down in motor neurons. This model exhibited severe motor defects together with axonal and neuronal degeneration. We also observed the impaired movement and increased number of autophagosomes in the degenerated neurons. Furthermore, the combination of rapamycin, an activator of autophagy, and trichostatin which facilitates axonal transport dramatically ameliorated the motor phenotype and axonal degeneration of this model. Thus, our results suggest that decreased expression of dynactin 1 induces motor neuron degeneration and that the transport of autophagosomes is a novel and substantial therapeutic target for motor neuron degeneration.

Topics: Amyotrophic Lateral Sclerosis; Animals; Drug Therapy, Combination; Dynactin Complex; Humans; Hydroxamic Acids; Microtubule-Associated Proteins; Molecular Targeted Therapy; Motor Neurons; Mutation; Phagosomes; Sirolimus

Topics: Acetylation; Amyotrophic Lateral Sclerosis; Epigenesis, Genetic; Frontotemporal Dementia; Histone Code; Histones; Humans; Hydroxamic Acids; Mutation; Neurons; Protein Aggregates; Protein Aggregation, Pathological; RNA-Binding Protein FUS; Saccharomyces cerevisiae

Recent studies suggest that progressive motoneuron death in amyotrophic lateral sclerosis (ALS) is non-cell autonomous and may involve the participation of non-neuronal cells such as glial cells and skeletal muscle. Therefore, a drug that targets motoneurons as well as neighboring non-neuronal cells might be a potential therapeutic strategy to delay disease progression in ALS. Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, has shown protective effects in multiple cell types implicated in ALS by resetting gene transcription profiles through increased histone acetylation. To test whether TSA could serve as a potential therapeutic agent, we intraperitoneally injected TSA from postnatal day 90 (P90), after disease symptoms appear, until P120 or the end-stage in SOD1-G93A mice. We found that TSA ameliorated motoneuron death and axonal degeneration in SOD1-G93A mice. Reduced gliosis and upregulation of the glutamate transporter (GLT-1) were also observed in the spinal cord of TSA-treated SOD1-G93A mice. In addition, TSA ameliorated muscle atrophy and neuromuscular junction (NMJ) denervation, which are the pathological characteristics of ALS found in skeletal muscle. Improved morphology in TSA-treated SOD1-G93A mice was accompanied by enhanced motor functions as assessed by rota-rod and grip strength analyses. Furthermore, TSA treatment significantly increased the mean survival duration after the treatment by 18% and prolonged lifespan by 7%. Our findings suggest that TSA may provide a potential therapy to slow disease progression as well as to enhance motor performance to improve the quality of life for ALS patients.

Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Disease Progression; Histone Deacetylase Inhibitors; Hydroxamic Acids; Male; Mice; Mice, Transgenic; Motor Neurons; Neuromuscular Junction; Spinal Cord; Survival Rate