Theresa A. Zesiewicz, George Wilmot, Sheng-Han Kuo, Susan Perlman, Patricia E. Greenstein, Sarah H. Ying, Tetsuo Ashizawa, S.H. Subramony, Jeremy D. Schmahmann, K.P. Figueroa, Hidehiro Mizusawa, Ludger Schöls, Jessica D. Shaw, Richard M. Dubinsky, Melissa J. Armstrong, Gary S. Gronseth and Kelly L. Sullivan. Neurology published online February 9, 2018 doi:10.1212/WNL.0000000000005055
Objective To systematically review evidence regarding ataxia treatment.
Methods A comprehensive systematic review was performed according to American Academy of Neurology methodology.
Conclusions For patients with episodic ataxia type 2, 4-aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are insufficient to support or refute the use of numerous agents. For nonpharmacologic options, in patients with degenerative ataxias, 4-week inpatient rehabilitation probably improves ataxia and function (1 Class I study); transcranial magnetic stimulation possibly improves cerebellar motor signs at 21 days (1 Class II study). For patients with multiple sclerosis–associated ataxia, the addition of pressure splints possibly has no additional benefit compared with neuromuscular rehabilitation alone (1 Class II study). Data are insufficient to support or refute use of stochastic whole-body vibration therapy (1 Class III study).
Thursday, February 15, 2018
Interactions of Frataxin with ISCU and Ferredoxin on the Cysteine Desulfurase Complex Leading to Fe-S Cluster Assembly
Kai Cai. Volume 114, Issue 3, Supplement 1, 2 February 2018, Pages 571a, doi:10.1016/j.bpj.2017.11.3123
Frataxin (FXN) is involved in mitochondrial iron-sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. We have used a combination of isothermal titration calorimetry, chemical cross-linking with analysis by LC/MS/MS, multinuclear NMR spectroscopy, and biochemical assays to investigate interactions among the components of the biological machine that carries out the assembly of iron-sulfur clusters in human mitochondria. We have constructed a structural model of the core of this machine by combining homology modeling with docking constraints derived from NMR chemical shift perturbations and chemical cross-linking studies. We show that the machinery operates through dynamic interactions among its components and have identified interactions relevant to the cysteine desulfurase reaction, which generates S, and iron transfer from FXN, which leads to iron-sulfur cluster assembly. We also have elucidated the mechanism by which the variant ISCU(M108I) bypasses the requirement for FXN.
Frataxin (FXN) is involved in mitochondrial iron-sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. We have used a combination of isothermal titration calorimetry, chemical cross-linking with analysis by LC/MS/MS, multinuclear NMR spectroscopy, and biochemical assays to investigate interactions among the components of the biological machine that carries out the assembly of iron-sulfur clusters in human mitochondria. We have constructed a structural model of the core of this machine by combining homology modeling with docking constraints derived from NMR chemical shift perturbations and chemical cross-linking studies. We show that the machinery operates through dynamic interactions among its components and have identified interactions relevant to the cysteine desulfurase reaction, which generates S, and iron transfer from FXN, which leads to iron-sulfur cluster assembly. We also have elucidated the mechanism by which the variant ISCU(M108I) bypasses the requirement for FXN.
RNA–DNA hybrids promote the expansion of Friedreich's ataxia (GAA)n repeats via break-induced replication
Alexander J Neil Miranda U Liang Alexandra N Khristich Kartik A Shah Sergei M Mirkin; Nucleic Acids Research, , gky099, doi:10.1093/nar/gky099
Expansion of simple DNA repeats is responsible for numerous hereditary diseases in humans. The role of DNA replication, repair and transcription in the expansion process has been well documented. Here we analyzed, in a yeast experimental system, the role of RNA–DNA hybrids in genetic instability of long (GAA)n repeats, which cause Friedreich’s ataxia. Knocking out both yeast RNase H enzymes, which counteract the formation of RNA–DNA hybrids, increased (GAA)n repeat expansion and contraction rates when the repetitive sequence was transcribed. Unexpectedly, we observed a similar increase in repeat instability in RNase H-deficient cells when we either changed the direction of transcription-replication collisions, or flipped the repeat sequence such that the (UUC)n run occurred in the transcript. The increase in repeat expansions in RNase H-deficient strains was dependent on Rad52 and Pol32 proteins, suggesting that break-induced replication (BIR) is responsible for this effect. We conclude that expansions of (GAA)n repeats are induced by the formation of RNA–DNA hybrids that trigger BIR. Since this stimulation is independent of which strand of the repeat (homopurine or homopyrimidine) is in the RNA transcript, we hypothesize that triplex H-DNA structures stabilized by an RNA–DNA hybrid (H-loops), rather than conventional R-loops, could be responsible.
Expansion of simple DNA repeats is responsible for numerous hereditary diseases in humans. The role of DNA replication, repair and transcription in the expansion process has been well documented. Here we analyzed, in a yeast experimental system, the role of RNA–DNA hybrids in genetic instability of long (GAA)n repeats, which cause Friedreich’s ataxia. Knocking out both yeast RNase H enzymes, which counteract the formation of RNA–DNA hybrids, increased (GAA)n repeat expansion and contraction rates when the repetitive sequence was transcribed. Unexpectedly, we observed a similar increase in repeat instability in RNase H-deficient cells when we either changed the direction of transcription-replication collisions, or flipped the repeat sequence such that the (UUC)n run occurred in the transcript. The increase in repeat expansions in RNase H-deficient strains was dependent on Rad52 and Pol32 proteins, suggesting that break-induced replication (BIR) is responsible for this effect. We conclude that expansions of (GAA)n repeats are induced by the formation of RNA–DNA hybrids that trigger BIR. Since this stimulation is independent of which strand of the repeat (homopurine or homopyrimidine) is in the RNA transcript, we hypothesize that triplex H-DNA structures stabilized by an RNA–DNA hybrid (H-loops), rather than conventional R-loops, could be responsible.
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