2 research outputs found
Genetic and epigenetic foundation of autism
Autizam je definiran kao poremećaj u razvitku mozga i živčanog sustava u kritičnom periodu.
Autizam, uz Rettov sindrom, Aspergerov sindrom i druge pripada u poremećaje autističnog
spektra. Temeljni simptomi autizma su teškoće u socijalnim ponašanjima, komunikaciji i
repetativna ponašanja, interesi i aktivnosti. Fenotip autizma je varijabilan i individualan što
čini proučavanje i otkrivanje patofiziologije kompliciranim. Kroz godine istraživanja
pokazalo se da je genetička komponenta vrlo jaka u autizmu. Identificirani su mnogi geni koji
su bitni za pravilan razvoj mozga, a u slučaju disfunkcije sudjeluju u razvoju autizma.
Nadalje, aktualna istraživanja pokazala su da i epigenski mehanizmi imaju značajnu ulogu u
nastanku autističnog poremećaja. Mehanizmi poput DNA metilacije ili histonske acetilacije
mogu utjecati na ekspresiju gena koji se smatraju rizičnim faktorima za autizam. Genski i
epigenski fiziološki putevi su isprepleteni i dvosmjerni, mogu utjecati zasebno na razvoj
autizma, ali i mogu utjecati jedan na drugoga i tako sudjelovati u razvoju autizma. Važno je
razumjeti da identificirani geni, epigenske promjene, kemijske neravnoteže i okolišni faktori
svi djeluju zajedno ili jedni na druge ili na razvoj živčanog sustava pridonoseći razvoju
autizma. Zbog opsežne količine dostupne literature, pisanje radova koji sažimaju informacije
o autizmu pridonijeti će istraživanjima i staviti u perspektivu trenutna znanjAutism is a neurodevelopmental disorder that falls under the Autistic spectre which
encompasess other disorders like Rett syndrome, Aspergers syndrome, etc... The core
symptoms of autistic disorder are: reduced social and communication abilities and repetative
behaviour, interests and actions. The phenotype for autism is extremely variable and
individual which makes understanding the patophysiology of the disorder difficult and
complex. Throughout yeras of reasearch it has been established that many autism cases have
a genetic cause. Specific genes have been identified which have an important role in
neurodevelopment and in autism cases were shown to be dysfunctional. Furthermore, recent
studies have shown the significance of epigenetics in autism reasearch. Epigenetic
mechanisms such as DNA methylation or histone acetylation have been proven to influence
gene expression of risk-factor genes for autism and expedite its development. Both genome
and epigenome physiological pathways are intertwined and can influence the progress of
autism development, but they can also influence each other in negative or positive ways. It is
important to understand, all the identified genes, epigenetic changes, chemical imbalances
and environmental factors work together and influence each other and neurodevelopment. As
there is a significant amount of literature available on the topic, writing reviews summarizing
all current data will be beneficial and will offer new perspective
Sequential treatment with a TNFR2 agonist and a TNFR1 antagonist improves outcomes in a humanized mouse model for MS
Abstract TNF signaling is an essential regulator of cellular homeostasis. Through its two receptors TNFR1 and TNFR2, soluble versus membrane-bound TNF enable cell death or survival in a variety of cell types. TNF-TNFRs signaling orchestrates important biological functions such as inflammation, neuronal activity as well as tissue de- and regeneration. TNF-TNFRs signaling is a therapeutic target for neurodegenerative diseases such as multiple sclerosis (MS) and Alzheimer’s disease (AD), but animal and clinical studies yielded conflicting findings. Here, we ask whether a sequential modulation of TNFR1 and TNFR2 signaling is beneficial in experimental autoimmune encephalomyelitis (EAE), an experimental mouse model that recapitulates inflammatory and demyelinating aspects of MS. To this end, human TNFR1 antagonist and TNFR2 agonist were administered peripherally at different stages of disease development in TNFR-humanized mice. We found that stimulating TNFR2 before onset of symptoms leads to improved response to anti-TNFR1 therapeutic treatment. This sequential treatment was more effective in decreasing paralysis symptoms and demyelination, when compared to single treatments. Interestingly, the frequency of the different immune cell subsets is unaffected by TNFR modulation. Nevertheless, treatment with only a TNFR1 antagonist increases T-cell infiltration in the central nervous system (CNS) and B-cell cuffing at the perivascular sites, whereas a TNFR2 agonist promotes Treg CNS accumulation. Our findings highlight the complicated nature of TNF signaling which requires a timely balance of selective activation and inhibition of TNFRs in order to exert therapeutic effects in the context of CNS autoimmunity