title: Impaired mTORC1-Dependent Expression of Homer-3 Influences SCA1 Pathophysiology.
abstract: Spinocerebellar ataxia type 1 (SCA1), due to the expansion of a polyglutamine repeat within the ubiquitously expressed Ataxin-1 protein, leads to the premature degeneration of Purkinje cells (PCs), the cause of which is poorly understood. Here, we identified the unique proteomic signature of Sca1(154Q/2Q) PCs at an early stage of disease, highlighting extensive alterations in proteins associated with synaptic functioning, maintenance, and transmission. Focusing on Homer-3, a PC-enriched scaffold protein regulating neuronal activity, revealed an early decline in its expression. Impaired climbing fiber-mediated synaptic transmission diminished mTORC1 signaling, paralleling Homer-3 reduction in Sca1(154Q/2Q) PCs. Ablating mTORC1 within PCs or pharmacological inhibition of mTORC1 identified Homer-3 as its downstream target. mTORC1 knockout in Sca1(154Q/2Q) PCs exacerbated and accelerated pathology. Reinstating Homer-3 expression in Sca1(154Q/2Q) PCs attenuated cellular dysfunctions and improved motor deficits. Our work reveals that impaired mTORC1-Homer-3 activity underlies PC susceptibility in SCA1 and presents a promising therapeutic target.
authors.affiliation: Institute of Cell Biology, University of Bern, Baltzerstrasse 4, CH-3012 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3012 Bern, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Ruegsegger
authors.affiliation: Institute of Cell Biology, University of Bern, Baltzerstrasse 4, CH-3012 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3012 Bern, Switzerland.
authors.forename: David M
authors.initials: DM
authors.lastname: Stucki
authors.affiliation: Institute of Cell Biology, University of Bern, Baltzerstrasse 4, CH-3012 Bern, Switzerland.
authors.forename: Silvio
authors.initials: S
authors.lastname: Steiner
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland.
authors.forename: Nico
authors.initials: N
authors.lastname: Angliker
authors.affiliation: Institute of Anatomy, University of Bern, Baltzerstrasse 2, CH-3012 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3012 Bern, Switzerland.
authors.forename: Julika
authors.initials: J
authors.lastname: Radecke
authors.affiliation: Institute of Cell Biology, University of Bern, Baltzerstrasse 4, CH-3012 Bern, Switzerland.
authors.forename: Eva
authors.initials: E
authors.lastname: Keller
authors.affiliation: Institute of Anatomy, University of Bern, Baltzerstrasse 2, CH-3012 Bern, Switzerland.
authors.forename: Benoît
authors.initials: B
authors.lastname: Zuber
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.affiliation: Institute of Cell Biology, University of Bern, Baltzerstrasse 4, CH-3012 Bern, Switzerland. Electronic address: smita.saxena@izb.unibe.ch.
authors.forename: Smita
authors.initials: S
authors.lastname: Saxena
mesh_terms: D000818:Animals; D000067696:Ataxin-1 / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002493:Central Nervous System Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000072233:Homer Scaffolding Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D011689:Purkinje Cells / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000067696:Ataxin-1; C000593750:Atxn1 protein, mouse; D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases