Protein instability and altered folding associated with ALS
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Transcript of Protein instability and altered folding associated with ALS
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There are 114 mutations in the geneencoding Cu/Zn superoxide dismutase(SOD) associated with amyotrophiclateral sclerosis (ALS). Misfolding andaggregation of mutant SOD1 werethought to be an essential part ofdisease progression in ALS. Now,researchers report a link betweenaltered folding patterns, proteinstability, net charge, and survival timein patients carrying the mutations.
“We selected the 15 mutations thathad the most reliable and sufficientclinical data available, and trackedthem in vitro, with respect to howthey folded”, explains study authorMikael Oliveberg (Umeå University,Umeå, Sweden). “All of the mutationsperturbed the folding pattern of theprotein. It is what we expected, but noone had ever shown it before.”
The cytotoxic component of severalneurodegenerative disorders, includingALS, Parkinson’s disease, and
Lund–Huntington’s disease, seems tobe ordered oligomeric states oraggregates of unfolded or misfoldedproteins. Oliveberg and colleaguesmapped out and compared the foldingbehaviour of ALS-associated mutantsand survival times to ascertain theorigin of neurotoxicity in ALS (Proc NatlAcad Sci 2005, published onlineJune 27, DOI: 50195710).
Oliveberg’s group assessed thekinetics of SOD1 monomer folding andunfolding, and of dimer association anddissociation, and showed that themutations increase the cellularconcentration of immature monomers.They also identified an associationbetween protein instability and diseaseprogression: the more unstable theprotein, the quicker the diseaseprogression. The protein is alsonegatively charged and reduction ofthe negative charge seems to decreasesurvival time.
For future clinical applications ofthese findings, Oliveberg points outthat protein stability is a major factor.“If you can design a drug that canstabilise the protein, you may be able toat least slow down the progression ofthe disease.”
This work supports the results of astudy by Ray and colleagues (Proc NatlAcad Sci USA 2005; 102: 3639–44)who identified molecules that stabilisethe SOD1 dimer interface, commentsLinda Greensmith (University CollegeLondon, UK). “Together the work ofthese two groups suggests a promisingmethod for the rational design ofpotential therapeutic compounds,which may shift the equilibrium ofmutant SOD1 protein folding in favourof the stable dimerised protein as ameans of delaying disease progressionin ALS”, she says.
Roxanne Nelson
462 http://neurology.thelancet.com Vol 4 August 2005
Protein instability and altered folding associated with ALS
Scientists have shown that coexistentgeneralised epilepsy and paroxysmaldyskinesia (GEPD) are linked tomutations in an ion channel gene,which suggests this disorder may be achannelopathy. Although not ascommon as epilepsy, paroxysmal dys-kinesia is also characterised by suddenattacks of involuntary movement.
Wei Du and colleagues (ClevelandClinic Foundation, Cleveland, OH, USA)genetically analysed a large family withGEPD and found that a mutation in aregion of chromosome 10q22 waslinked with the disorder (Nat Genet2005; published online June 5,DOI:10.1038/ng1585). The researcherssuggest that such mutations could bethe underlying cause of GEPD.
Du and colleagues went on to identifya mutation in one such gene, KCNMA1,which encodes the pore-forming �subunit of the big potassium ion (BK)channel, in the study family. The
mutation results in the substitution ofaspartic acid with glycine (Asp434Gly)and disrupts normal calcium ion affinityand BK channel activation.
Additionally, more current wasinduced at the same membranepotential in mutant BK channels thanin wild-type channels. The researcherspostulated that during an actionpotential, more mutant than wild-type channels open in response todepolarisation and calcium ion entry,which causes a fast repolarisation.Notably, mutant channels were moresensitive to calcium than wild-typechannels, by contrast with otherknown mutations of the � subunit,which reduce calcium sensitivity.
Du’s team concludes that raisedcalcium sensitivity could result in anincrease in potassium conductance ofthe BK channel, brain excitability, and,ultimately, GEPD. "Our study providesstrong genetic evidence confirming
that coexistent epilepsy and [parox-ysmal dyskinesia] indeed represent adistinct syndrome (GEPD)”, states corr-esponding author Qing Wang. Theyalso suggest that Asp434Gly is a gain-of-function mutation, with a possiblesynergistic effect with ethanol to triggerGEPD. Thus BK channels could betargeted for treatment.
This study “confirms that the list ofchannels implicated in monogenicneurological disease is not exhausted”,comments Dimitri Kullmann (Instituteof Neurology, University CollegeLondon, UK). “Given that there areseveral hundred ion-channel genesexpressed in the brain, and only a dozenor so known CNS channelopathies,there are probably many more channel-opathies to be identified. Nevertheless”,he adds, “some of these might onlyaffect very small numbers of families”.
Vivien Chen
Channelopathy linked to epilepsy and paroxysmal dyskinesia