Spinal Muscular Atrophy .28SMA.29 Epigenetics of neurodegenerative diseases

alpha motor neurons derived basal plate (basal lamina).

spinal muscular atrophy (sma) autosomal recessive motor neuron disease caused mutations in smn1 gene (brzustowicz et al., 1990). symptoms vary each subset of sma , stage of disease. general symptoms include overall muscle weakness , poor muscle tone including extremities , respiratory muscles leading difficulty walking, breathing, , feeding. depending on type of sma, disease can present infancy through adulthood. smn protein promotes survival of motor neurons, mutations in smn1 results in slow degeneration motor neurons leading progressive system-wide muscle wasting. specifically, on time, decreased levels of smn protein results in gradual death of alpha motor neurons in anterior horn of spinal cord , brain. muscles depend on connections motor neurons , central nervous system stimulate muscle maintenance , therefore degeneration of motor neurons , subsequent denervation of muscles lead loss of muscle control , muscle atrophy. muscles of lower extremities affected first followed upper extremities , sometime muscles of respiration , mastication. in general, proximal muscle affected more distal muscle.

genetic cause

spinal muscular atrophy linked genetic mutations in smn1 (survival of motor neuron 1) gene. smn protein expressed in neurons , serves many functions within neurons including spliceosome construction, mrna axon transport, neurite outgrowth during development, , neuromuscular junction formation. causal function loss in sma unknown.

smn1 located in telomeric region of human chromosome 5 , contains smn2 in centromeric region. smn1 , smn2 identical except single nucleotide change in smn2 resulting in alternative splicing site intron 6 meets exon 8. single base pair change leads 10-20% of smn2 transcripts resulting in functional smn protein , 80-90% of transcripts leading truncated protein rapidly degraded. sma patients have 2 or more copies of smn2 gene more copies resulting decrease in disease severity (prior et al., 2009). sma patients have either point mutations or deletion in exon 7 leading protein product similar truncated , degraded version of smn2 protein. in sma patients small amount of functional smn2 protein product allows neurons survive.

epigenetic treatment through smn2 gene activation

although sma not caused epigenetic mechanism, therapeutic drugs target epigenetic marks may provide sma patients relief, halting or reversing progression of disease. sma patients higher copy numbers of smn2 gene have less severe symptoms, researchers predicted epigenetic drugs increased smn2 mrna expression increase amount of functional smn protein in neurons leading reduction in sma symptoms. histone deacetylase (hdac) inhibitors main compounds have been tested increase smn2 mrna expression. inhibiting hdacs allow hyperacetylation of smn2 gene loci theoretically resulting in increase in smn2 expression (kernochan et al., 2005). many of these hdac inhibitors (hdaci) first tested in mouse models of sma created through variety of mutations in mouse smn1 gene. if mice show improvement , drug not cause many side effects or toxicity, drug may used in human clinical trials. human trials of below hdac inhibitors extremely variable , impacted patient s exact sma subtype.