Amyotrophic lateral sclerosis .28ALS.29 Epigenetics of neurodegenerative diseases

amyotrophic lateral sclerosis (als), known lou gehrig’s disease, motor neuron disease involves neurogeneration. skeletal muscles in body controlled motor neurons communicate signals brain muscle through neuromuscular junction. when motor neurons degenerate, muscles no longer receive signals brain , begin waste away. als characterized stiff muscles, muscle twitching, , progressive muscle weakness muscle wasting. parts of body affected symptoms of als depend on motor neurons in body damaged first, limbs. disease progresses patients unable walk or use arms , develop difficulty speaking, swallowing , breathing. patients retain cognitive function , sensory neurons unaffected. patients diagnosed after age of 40 , median survival time onset death around 3–4 years. in final stages, patients can lose voluntary control of eye muscles , die of respiratory failure or pneumonia result of degeneration of motor neurons , muscles required breathing. there no cure als, treatments may prolong life.

genetics , underlying causes

to date, multiple genes , proteins have been implicated in als. 1 of common themes between many of these genes , causative mutations presence of protein aggregates in motor neurons (dewey et al., 2012). other common molecular features in als patients altered rna metabolism (polymenidou et al., 2012) , general histone hypoacetylation (rouaux et al., 2003).

sod1

chromossome 21



the sod1 gene on chromosome 21 codes superoxide dismutase protein associated 2% of cases , believed transmitted in autosomal dominant manner (battistini et al., 2009; anderson et al., 1996). many different mutations in sod1 have been documented in als patients varying degrees of progressiveness (anderson et al., 1996). sod1 protein responsible destroying naturally occurring, harmful superoxide radicals produced mitochondria. of sod1 mutations associated als gain-of-function mutations in protein retains enzymatic activity, aggregate in motor neurons causing toxicity (bruijn et al., 1998; furukawa et al., 2006). normal sod protein implicated in other cases of als due potentially cellular stress (boillee et al., 2006). researchers have developed als mouse model through gain-of-function mutations in sod1 (cudkowicz et al., 1997).

c9orf72

recently gene called c9orf72 found have hexanucleotide repeat in non-coding region of gene in association als , als-ftd (dejesus-hernandez et al., 2011; renton et al., 2011; majounie et al., 2012). these hexanucleotide repeats may present in 40% of familial als cases , 10% of sporadic cases. c9orf72 functions guanine exchange factor small gtpase, not related underlying cause of als (yoshimura et al., 2010). hexanucleotide repeats causing cellular toxicity after spliced out of c9orf72 mrna transcripts , accumulate in nuclei of affected cells (lee et al., 2013).

ubqln2

the ubqln2 gene encodes protein ubiquilin 2 responsible controlling degradation of ubiquitinated proteins in cell. mutations in ubqln2 interfere protein degradation resulting in neurodegeneration through abnormal protein aggregation (han-xiang et al., 2011). form of als x chromosome-linked , dominantly inherited , can associated dementia.

epigenetic treatment hdac inhibitors

als patients , mouse models show general histone hypoacetylation can trigger apoptosis of cells (rouaux et al., 2004). in experiments mice, hdac inhibtors counteract hypoacetylation, reactivate aberrantly down-regulated genes, , counteract apoptosis initiation (ryu et al., 2005; yoo et al., 2011). furthermore, hdac inhibitors known prevent sod1 protein aggregates in vitro (corcoran et al., 2004).

sodium phenylbutyrate

sodium phenylbutyrate treatment in sod1 mouse model of als showed improved motor performance , coordination, decreased neural atrophy , neural loss, , increased weight gain (del signore et al., 2009; petri et al., 2006). release of pro-apoptotic factors abrogated general increase in histone acetylation (ryu et al., 2005). human trial using phenylbuturate in als patients showed increase in histone acetylation, study did not report whether als symptoms improved treatment (cudkowicz et al., 2009).

valproic acid

valproic acid in mice studies restored histone acetylation levels, increased levels of pro-survival factors, , mice showed improved motor performance (crochemore et al., 2009). however, while drug delayed onset of als, did not increase lifespan or prevent denervation (rouaux et al., 2007). human trials of valproic acid in als patients did not improve survival or slow progression (piepers et al., 2009).

trichostatin a

trichostatin trials in mouse als models restored histone acetylation in spinal neurons, decreased axon demyelination, , increased survival of mice (yoo et al., 2011).