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DTSTAMP:20260404T194107Z
UID:1624021200@ist.ac.at
DTSTART:20210618T150000
DTEND:20210618T160000
DESCRIPTION:Speaker: Michael Freissmuth\nhosted by Chaitanya Chintaluri\nAb
 stract: Diseases that arise from misfolding of an individual protein are r
 are. However\, collectively\, these folding diseases represent a large pro
 portion of hereditary and acquired disorders. In fact\, the term "Molecula
 r Medicine" was coined by Linus Pauling in conjunction with the study of a
  folding disease\, i.e. sickle cell anemia. In the past decade\, we have w
 itnessed an exponential growth in the number of mutations\, which have bee
 n identified in genes encoding solute carriers (SLC). A sizable faction - 
 presumably the majority - of these mutations result in misfolding of the e
 ncoded protein. While studying the export of the GABA transporter (SLC6A1)
  and of the serotonin transporter (SLC6A4)\, from the endoplasmic reticulu
 m (ER)\, we discovered by serendipity that some ligands can correct the fo
 lding defect imparted by point mutations. These bind to the inward facing 
 state. The most effective compound is noribogaine\, the metabolite of ibog
 aine (an alkaloid first isolated from the shrubTabernanthe iboga). There a
 re 13 mutations in the human dopamine transporter (DAT\, SLC6A3)\, which g
 ive rise to a syndrome of infantile Parkinsonism and dystonia. We capitali
 zed on our insights to explore\, if the disease-relevant mutant proteins w
 ere amenable to pharmacological correction. Drosopohila melanogaster\, whi
 ch lack the dopamine transporter\, are hyperactive and sleepless (fumin in
  Japanese). Thus\, mutated human DAT variants can be introduced into fumin
  flies. This allows for examining the effect of pharmacochaperones on deli
 very of DAT to the axonal territory and on restoring sleep. We explored th
 e chemical space populated by variations of the ibogaine structure to ide
 ntify an analogue (referred to as compound 9b)\, which was highly effectiv
 e: compound 9b also restored folding in DAT variants\, which were not amen
 able to rescue by noribogaine. Deficiencies in the human creatine transpor
 ter-1 (CrT1\, SLC6A8) give rise to a syndrome of intellectual disability a
 nd seizures and accounts for 5% of genetically based intellectual disabili
 ties in boys. Point mutations occur\, in part\, at positions\, which are h
 omologous to those of folding-deficient DAT variants. CrT1 lacks the rich 
 pharmacology of monoamine transporters. Nevertheless\, our insights are al
 so applicable to rescuing some disease-related variants of CrT1. Finally\,
  the question arises how one can address the folding problem. We propose a
  two-pronged approach: (i) analyzing the effect of mutations on the transp
 ort cycle by electrophysiological recordings\; this allows for extracting 
 information on the rates of conformational transitions. The underlying ass
 umption posits that - even when remedied by pharmacochaperoning - folding-
 deficient mutants must differ in the conformational transitions associated
  with the transport cycle. (ii) analyzing the effect of mutations on the t
 wo components of protein stability\, i.e. thermodynamic and kinetic stabil
 ity. This is expected to provide a glimpse of the energy landscape\, which
  governs the folding trajectory.
LOCATION:Central Building\, Lecture Hall\, ISTA
ORGANIZER:
SUMMARY:Michael Freissmuth: Sleepless in Vienna - how to rescue folding-def
 icient dopamine transporters by  pharmacochaperoning
URL:https://talks-calendar.ista.ac.at/events/3209
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