Neurodegenerative Diseases of the Central Nervous System Epigenetics of neurodegenerative diseases

1 neurodegenerative diseases of central nervous system

1.1 alzheimer’s disease (ad)
1.2 huntington s (hd)
1.3 parkinson s disease (pd)

neurodegenerative diseases of central nervous system
alzheimer’s disease (ad)

main wiki article: alzheimer’s disease

alzheimer’s disease (ad) prevalent form of dementia among elderly. disease characterized behaviorally chronic , progressive decline in cognitive function, beginning short term memory loss, , neurologically buildup of misfolded tau protein , associated neurofibrillary tangles, , amyloid-beta senile plaques amyloid-beta senile plaques. several genetic factors have been identified contributing ad, including mutations amyloid precursor protein (app) , presenilins 1 , 2 genes, , familial inheritance of apolipoprotein e allele epsilon 4. in addition these common factors, there number of other genes have shown altered expression in alzheimer s disease, of associated epigenetic factors.

epigenetic factors of alzheimer’s disease

ncrna

research has shown ncrna encoded antisense intron within beta-amyloid cleaving enzyme gene, bace1, involved in ad (faghihi et al., 2008). ncrna, bace1-as (for antisense), overlaps exon 6 of bace1, involved in increasing stability of bace1 mrna transcript. gene s name suggests, bace1 enzymatic protein cleaves amyloid precursor protein insoluble amyloid beta form, aggregates senile plaques. increased stability of bace1 mrna resulting bace1-as, more bace1 mrna available translation bace1 protein.






mirna factors have not consistently been shown play role in progression of ad. mirnas involved in post-transcriptional gene silencing via inhibiting translation or involvement in rnai pathways. studies have shown upregulation of mirna-146a, differentially regulates neuroimmune-related interleukin-1r associated kinases irak1 , irak2 expression, in human ad brain, while other studies have shown upregulation or downregulation of mirna-9 in brain (bennett et al., 2015).




dna methylation

in alzheimer’s disease cases, global dna hypomethylation , gene-specific hypermethylation has been observed, though findings have varied between studies, in studies of human brains. hypothetically, global hypomethylation should associated global increases in transcription, since cpg islands prevalent in gene promoters; gene-specific hypermethylation, however, indicate these hypermethylated genes repressed methylation marks. generally, repressive hypermethylation of genes related learning , memory has been observed in conjunction derepressive hypomethylation of neuroinflammatory genes , genes related pathological expression of alzheimer s disease.




brain-derived neurotrophic factor





one study has shown reduced methylation in long-term memory-associated temporal neocortex neurons in monozygotic twins alzheimer’s disease compared healthy twin (mastroeni et al., 2009). global hypomethylation of cpg dinucleotides has been observed in hippocampus (chouliaras et al., 2013) , in entorhinal cortex layer ii (mastroeni et al., 2010) of human ad patients, both of susceptible ad pathology. these results, found probing immunoassays, have been challenged studies interrogate dna sequence bisulfite sequencing, cpg transformation technique sensitive cpg methylation status, in global hypomethylation has been observed (bakulski et al., 2012; rao et al., 2012).






at individual gene level, rao et al. have reported hypomethylation , derepression of cox-2, inhibition of reduces inflammation , pain, , hypermethylation of bdnf, neurotrophic factor important long-term memory. expression of creb, activity-dependent transcription factor involved in regulating bdnf among many other genes, has been shown hypermethylated, , repressed, in ad brains, further reducing bdnf transcription (rao et al., 2012). furthermore, synaptophysin (syp), major synaptic vesicle protein-encoding gene, has been shown hypermethylated , repressed, , transcription factor nf-κb, involved in immune signaling, has been shown hypomethylated , derepressed (rao et al., 2012). taken together, these results have elucidated role dysregulation of genes involved in learning , memory , synaptic transmission, immune response.






hypomethylation has been observed in promoters of presenilin 1 (wang et al., 2008), gsk3beta, phosphorylates tau protein (nicolia et al., 2010), , bace1 (byun et al., 2012), enzyme cleaves app amyloid-beta form, in turn aggregates insoluble senile plaques. repressive hypermethylation caused amyloid-beta has been observed @ promoter of nep, gene neprilysin, major amyloid-beta clearing enzyme in brain (chen et al., 2009). repression of nep result in feed-forward buildup of senile plaques; combined observed increase in ad brains of bace1-as , corresponding increases in bace1 protein , amyloid beta (faghihi et al., 2008; see above), multiple levels of epigenetic regulation may involved in controlling amyloid-beta formation, clearance or aggregation, , senile plaque deposition.






there may effect of age in levels of dna methylation @ specific gene promoters, 1 study found greater levels of methylation @ app promoters in ad patients 70 years old, lower levels of methylation in patients greater 70 years old (tohgi et al., 1999). studies on differential dna methylation in human ad brains remain largely inconclusive possibly owing high degree of variability between individuals , numerous combinations of factors may lead ad.




histone marks

acetylation of lysine residues on histone tails typically associated transcriptional activation, whereas deacetylation associated transcriptional repression. there few studies investigating specific histone marks in ad. these studies have elucidated decrease in acetylation of lysines 18 , 23 on n-terminal tails of histone 3 (h3k18 , h3k23, respectively) (zhang et al., 2012) , increases in hdac2 in ad brains (graff et al., 2012) - both marks related transcriptional repression. age-related cognitive decline has been associated deregulation of h4k12 acetylation, cognitive effect restored in mice induction of mark (peleg et al., 2010).

treatments epigenetic factors of alzheimer’s disease treatment prevention or management of alzheimer s disease has proven troublesome since disease chronic , progressive, , many epigenetic drugs act globally , not in gene-specific manner. other potential treatments prevent or ameliorate symptoms of ad, these therapies not work cure, ameliorate symptoms of disease temporarily, underscoring chronic, progressive nature of ad, , variability of methylation in ad brains.

dna methylation-directed treatments

folate , other b vitamins

b vitamins involved in metabolic pathway leads sam production. sam donor of methyl group utilized dna methyltransferases (dnmts) methylate cpgs. using animal models, fuso et al. have demonstrated restoration of methylation @ hypomethylated promoters of presenilin 1, bace1 , app (fuso et al., 2005, 2008, 2012) - hypothetically stable epigenetic modification should repress genes , slow progression of ad. dietary sam supplementation has been shown reduce oxidative stress , delay buildup of neurological hallmarks of ad such amyloid beta , phosphorylated tau protein in transgenic ad mice.




aza

khan , colleagues have demonstrated potential role neuroglobinin attenuating amyloid-related neurotoxicity (khan et al., 2007). 5-aza-2 deoxycitidine (aza, or decitabine), dnmt inhibitor, has shown evidence regulating neuroglobin expression, though finding has not been tested in ad models (zhang et al., 2011).

histone-directed treatments

though studies of histone marks in ad brains few in number, several studies have looked @ effects of hdacis in treatment of alzheimer’s disease. class , ii hdac inhibitors such trichostatin a, vorinostat, , sodium butyrate, , class iii hdacis, such nicotinamide, have been effective @ treating symptoms in animal models of ad. while promising therapeutic in animal models, studies on long-term efficacy of hdacis , human trials have yet conducted.


sodium butyrate

sodium butyrate class , ii hdaci , has been shown recover learning , memory after 4 weeks (fischer et al., 2007), decrease phosphorylated tau protein, , restore dendritic spine density in hippocampus of ad transgenic mice (ricobaraza et al., 2010). histone acetylation resulting diffuse sodium butyrate application prevalent in hippocampus, , genes involved in learning , memory showed increased acetylation in ad mice treated drug (govindarajan et al., 2011).




trichostatin a

trichostatin class , ii hdaci rescues fear learning in fear conditioning paradigm in transgenic ad mice wild type levels via acetylation on histone 4 lysine tails (francis et al., 2009)




vorinostat

vorinostat class , ii hdaci has been shown effective @ inhibiting hdac2 , restoring memory functions in non-ad models of learning deficits (guan et al., 2009). 1 study showed vorinostat effective @ reversing contextual memory deficits in transgenic ad mice (kilgore et al., 2010).




huntington s (hd)

main wiki article: huntington s disease


this transverse section of striatum structural mr image. striatum, in red, includes caudate nucleus (top), putamen (right), and, when including term corpus striatum, globus pallidus (lower left).

huntington’s disease (hd) inherited disorder causes progressive degeneration of neurons within cerebral cortex , striatum of brain (omim 143100) resulting in loss of motor functions (involuntary muscle contractions), decline in cognitive ability (eventually resulting in dementia), , changes in behavior (urdinguio et al., 2009).

genetics , underlying causes

huntington’s caused autosomal dominant mutation expanding number of glutamine codon repeats (cag) within huntingtin gene (htt)(omin 613004) (http://www.omim.org/entry/143100). htt gene encodes huntingtin protein plays role in normal development exact function remains unknown (nasir et al., 1995). length of cag repeat correlates age-of-onset of disease. average person without huntington’s has less 36 cag repeats present within htt gene. when repeat length exceeds 36, onset of neuronal degradation , physical symptoms of huntington’s can range 5 years of age (cag repeat > 70) late 80 years of age (cag repeat < 39) (chen et al., 2002).

this cag expansion results in mrna downregulation of specific genes, decreased histone acetylation, , increased histone methylation (ryu et al., 2006; hazeki et al., 2002). exact mechanism of how repeat causes gene dysregulation unknown, epigenome modification may play role. early-onset huntington s (ages 5–15), both transgenic mice , mouse striatal cell lines show brain specific histone h3 hypoacetylation , decreased histone association @ specific downregulated genes within striatum (namely bdnf, cnr1, drd2 - dopamine 2 receptor, , penk1 - preproenkephalin) (sadri et al., 2007). both late- , early-onset huntington’s, h3 , h4 core histones associated these downregulated genes in htt mutants have hypoacetylation (decreased acetylation) compared wild-type htt (hazeki et al., 2002; sadri et al., 2007). hypoacetylation sufficient cause tighter chromatin packing , mrna downregulation (hazeki et al., 2002).

along h3 hypoacetylation, both human patients , mice mutant htt have increased levels of histone h3 lysine 9 trimethylation (ryu et al., 2006). increase in h3-k9 trimethylation linked increased expression of methyltransferase eset/setdb1 (erg-associated protein set domain (eset)), targets , trimethylates h3-k9 residues (ryu et al., 2006). it’s proposed hypermethylation may account onset of specific gene repression in htt mutants (ryu et al., 2006).

epigenetic treatment hdac inhibitors

huntington patients , both mouse , drosophila models show histone h3 , h4 hypoacetylation. there no treatments disease numerous hdac inhibitors have been tested , shown reverse symptoms caused htt mutation.

parkinson s disease (pd)

main wiki article: parkinson s disease


lewy bodies

parkinson’s disease (pd) characterized progressive degeneration of dopaminergic neurons in substantia nigra causes unknown. several genes , environmental factors (e.g. pesticide exposure) may play role in onset of pd. hallmarks include mutations alpha-synuclein gene, snca, park2, pink1, uchl1, dj1, , lrrk2 genes, , fibrillar accumulation of lewy bodies misfolded alpha-synuclein. symptoms noticeably manifested in disorders of movement, including shaking, rigidity, deficits in making controlled movements, , slow , difficult walking. late stages of disease result in dementia , depression. levodopa , dopaminergic therapy may ameliorate symptoms, though there no treatment halt progression of disease.

epigenetic factors of parkinson’s disease

ncrna

research has shown reductions of mir-133b correlated decreased numbers of dopaminergic neurons in midbrain of pd patients (kim et al., 2007). mir-132, meanwhile, negatively correlated dopaminergic neuron differentiation in midbrain (jankovic et al., 2005). mir-7 , mir-153 act reduce alpha-synuclein levels (a hallmark of pd) reduced in pd brain (doxakis, 2010).




dna methylation

neurons of pd patients show hypomethylation of tumor necrosis factor (tnf) alpha encoding sequence, overexpression of leads apoptosis of neurons (pieper et al., 2008). cerebrospinal fluid of pd patients shows elevated tnf alpha (mogi et al., 1996). research indicates there may link between dna methylation , snca expression (bonsch et al., 2005; jowaed et al., 2010). furthermore, human , mouse models have shown reduction of nuclear dnmt1 levels in pd subjects, resulting in hypomethylated states associated transcriptional repression (desplats et al., 2011).




histone marks

alpha-synuclein, protein encoded snca, can associate histones , prevent acetylation in concert hdacs hdac1 , sirt2 (kontopoulos et al., 2006; outeiro et al., 2007). furthermore, has been demonstrated alpha-synuclein binds histone 3 , inhibits acetylation in drosophila (kontopoulos et al., 2006). dopamine depletion in parkinson’s disease associated repressive histone modifications, including reduced h3k4me3, , lower levels of h3 , h4 lysine acetylation after levodopa therapy (a common treatment of pd).

treatments epigenetic factors of parkinson’s disease epigenetic treatments tested in models of pd few, though promising research has been conducted. treatments investigated far directed @ histone modifications , analysis of roles in mediating alpha-synuclein expression , activity. pesticides , paraquat increase histone acetylation, producing neurotoxic effects similar seen in pd, such apoptosis of dopaminergic cells (song et al., 2010, 2011). despite this, treatment hdacis (harrison , dexter, 2013) seems have neuroprotective effect.