title: Selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2.
abstract: Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by a polyglutamine expansion within the Ataxin-2 (Atxn2) protein. Purkinje cells (PC) of the cerebellum fire irregularly and eventually die in SCA2. We show here that the type 2 small conductance calcium-activated potassium channel (SK2) play a key role in control of normal PC activity. Using cerebellar slices from transgenic SCA2 mice we demonstrate that SK channel modulators restore regular pacemaker activity of SCA2 PCs. Furthermore, we also show that oral delivery of a more selective positive modulator of SK2/3 channels (NS13001) alleviates behavioral and neuropathological phenotypes of aging SCA2 transgenic mice. We conclude that SK2 channels constitute a therapeutic target for SCA2 treatment and that the developed selective SK2/3 modulator NS13001 holds promise as a potential therapeutic agent for treatment of SCA2 and possibly other cerebellar ataxias.
authors.affiliation: Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Adebimpe W
authors.initials: AW
authors.lastname: Kasumu
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hougaard
authors.forename: Frederik
authors.initials: F
authors.lastname: Rode
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Jacobsen
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Sabatier
authors.forename: Birgitte L
authors.initials: BL
authors.lastname: Eriksen
authors.forename: Dorte
authors.initials: D
authors.lastname: Strøbæk
authors.forename: Xia
authors.initials: X
authors.lastname: Liang
authors.forename: Polina
authors.initials: P
authors.lastname: Egorova
authors.forename: Dasha
authors.initials: D
authors.lastname: Vorontsova
authors.forename: Palle
authors.initials: P
authors.lastname: Christophersen
authors.forename: Lars Christian B
authors.initials: LC
authors.lastname: Rønn
authors.forename: Ilya
authors.initials: I
authors.lastname: Bezprozvanny
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011689:Purkinje Cells / Q000187:drug effects* / Q000502:physiology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000737:chemistry* / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: C579123:4-(chlorophenyl)-(2-(3,5-dimethylpyrazol-1-yl)-9-methyl-9H-purin-6-yl)amine; C496898:Kcnn2 protein, mouse; C496900:Kcnn3 protein, mouse; D011720:Pyrazoles; D051640:Small-Conductance Calcium-Activated Potassium Channels; D000225:Adenine; D002118:Calcium