Biomaterial Database

Karyopherin α-3 is a key protein in the pathogenesis of spinocerebellar ataxia type 3 controlling the nuclear localization of ataxin-3. 2018

Anna Sergeevna Sowa, and Elodie Martin, and Inês Morgado Martins, and Jana Schmidt, and Reinhard Depping, and Jonasz Jeremiasz Weber, and Franziska Rother, and Enno Hartmann, and Michael Bader, and Olaf Riess, and Hervé Tricoire, and Thorsten Schmidt

Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany.

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a CAG expansion in the ATXN3 gene leading to a polyglutamine expansion in the ataxin-3 protein. The nuclear presence and aggregation of expanded ataxin-3 are critical steps in disease pathogenesis. To identify novel therapeutic targets, we investigated the nucleocytoplasmic transport system by screening a collection of importins and exportins that potentially modulate this nuclear localization. Using cell, Drosophila, and mouse models, we focused on three transport proteins, namely, CRM1, IPO13, KPNA3, and their respective Drosophila orthologs Emb, Cdm, and Kap-α3. While overexpression of CRM1/Emb demonstrated positive effects in Drosophila, KPNA3/Kap-α3 emerged as the most promising target, as knockdown via multiple RNAi lines demonstrated its ability to shuttle both truncated and full-length expanded ataxin-3, rescue neurodegeneration, restore photoreceptor formation, and reduce aggregation. Furthermore, KPNA3 knockout in SCA3 mice resulted in an amelioration of molecular and behavioral disturbances such as total activity, anxiety, and gait. Since KPNA3 is known to function as an import protein and recognize nuclear localization signals (NLSs), this work unites ataxin-3 structure to the nuclear pore machinery and provides a link between karyopherins, NLS signals, and polyglutamine disease, as well as demonstrates that KPNA3 is a key player in the pathogenesis of SCA3.

UI	MeSH Term	Description	Entries
D008297	Male		Males
D010455	Peptides	Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are considered to be larger versions of peptides that can form into complex structures such as ENZYMES and RECEPTORS.	Peptide,Polypeptide,Polypeptides
D004195	Disease Models, Animal	Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases.	Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004330	Drosophila	A genus of small, two-winged flies containing approximately 900 described species. These organisms are the most extensively studied of all genera from the standpoint of genetics and cytology.	Fruit Fly, Drosophila,Drosophila Fruit Flies,Drosophila Fruit Fly,Drosophilas,Flies, Drosophila Fruit,Fly, Drosophila Fruit,Fruit Flies, Drosophila
D005260	Female		Females
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000067699	Ataxin-3	A deubiquitinating enzyme of the ATAXINS family. It functions in protein homeostasis, GENETIC TRANSCRIPTION; CYTOSKELETON regulation, and MYOGENESIS. CAG TRINUCLEOTIDE REPEAT EXPANSION in the Ataxin-3 gene coding region is associated with spinocerebellar ataxia-3 (MACHADO-JOSEPH DISEASE).	ATXN3 Protein,Ataxin-3 Protein,Machado-Joseph Disease Protein,SCA3 Protein,Spinocerebellar Ataxia 3 Protein,Ataxin 3,Ataxin 3 Protein,Machado Joseph Disease Protein
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D042622	DNA Repeat Expansion	An increase number of repeats of a genomic, tandemly repeated DNA sequence from one generation to the next.	Expanded DNA Repeats,DNA Repeat Expansions,DNA Repeat, Expanded,DNA Repeats, Expanded,Expanded DNA Repeat,Expansion, DNA Repeat,Expansions, DNA Repeat,Repeat Expansion, DNA,Repeat Expansions, DNA,Repeat, Expanded DNA,Repeats, Expanded DNA
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus