Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Local regulation of protein synthesis in neurons has emerged as a leading research focus because of its importance in synaptic plasticity and neurological diseases. The complexity of neuronal subcellular domains and their distance from the soma demand local spatial and temporal control of protein synthesis. Synthesis of many synaptic proteins, such as GluR and PSD-95, is under local control. mRNA binding proteins (RBPs), such as FMRP, function as key regulators of local RNA translation, and the mTORC1 pathway acts as a primary signaling cascade for regulation of these proteins. Much of the regulation occurs through structures termed RNA granules, which are based on reversible aggregation of the RBPs, some of which have aggregation prone domains with sequence features similar to yeast prion proteins. Mutations in many of these RBPs are associated with neurological diseases, including FMRP in fragile X syndrome; TDP-43, FUS (fused in sarcoma), angiogenin, and ataxin-2 in amyotrophic lateral sclerosis; ataxin-2 in spinocerebellar ataxia; and SMN (survival of motor neuron protein) in spinal muscular atrophy.
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PMID:Local RNA translation at the synapse and in disease. 2207 60

Interest in senataxin biology began in 2004 when mutations were first identified in what was then a novel protein. Dominantly inherited mutations were documented in rare juvenile-onset, motor neuron disease pedigrees in a familial form of amyotrophic lateral sclerosis (ALS4), while recessive mutations were found to cause a severe early-onset ataxia with oculomotor apraxia (AOA2) that is actually the second most common recessive ataxia after Freidreich's ataxia. From earlier studies of sen1p, the yeast ortholog of senataxin, a range of important RNA processing functions have been attributed to this protein. Like sen1p, senataxin contains a helicase domain to interact with RNA and an amino-terminal domain for critical protein interactions. Senataxin also joins a group of important proteins responsible for maintaining RNA transcriptome homeostasis, including FUS, TDP-43, and SMN that can all cause familial forms of motor neuron disease (MND). Independent of this association, senataxin is gaining attention for its role in maintaining genomic stability. Senataxin has been shown to resolve R-Loop structures, which form when nascent RNA hybridizes to DNA, displacing the non-transcribed strand. But in cycling cells, senataxin is also found at nuclear foci during the S/G2 cell-cycle phase, and may function at sites of specific collision between components of the replisome and transcription machinery. Which of these important processes is most critical to prevent neurodegeneration remains unknown, but our evolving understanding of these processes will be crucial not only for understanding senataxin's role in neurological disease, but also in a number of fundamentally important cellular functions.
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PMID:Unwinding the role of senataxin in neurodegeneration. 2572 27

The carboxy-terminal domain (CTD) of the RNA polymerase II (RNAP II) subunit POLR2A is a platform for modifications specifying the recruitment of factors that regulate transcription, mRNA processing, and chromatin remodelling. Here we show that a CTD arginine residue (R1810 in human) that is conserved across vertebrates is symmetrically dimethylated (me2s). This R1810me2s modification requires protein arginine methyltransferase 5 (PRMT5) and recruits the Tudor domain of the survival of motor neuron (SMN, also known as GEMIN1) protein, which is mutated in spinal muscular atrophy. SMN interacts with senataxin, which is sometimes mutated in ataxia oculomotor apraxia type 2 and amyotrophic lateral sclerosis. Because POLR2A R1810me2s and SMN, like senataxin, are required for resolving RNA-DNA hybrids created by RNA polymerase II that form R-loops in transcription termination regions, we propose that R1810me2s, SMN, and senataxin are components of an R-loop resolution pathway. Defects in this pathway can influence transcription termination and may contribute to neurodegenerative disorders.
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PMID:SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination. 2670 Aug 5