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Neuron. 2016 Jan 6;89(1):129-46. doi: 10.1016/j.neuron.2015.11.033.

Impaired mTORC1-Dependent Expression of Homer-3 Influences SCA1 Pathophysiology.

Author information

1
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.
2
Institute of Cell Biology, University of Bern, Baltzerstrasse 4, CH-3012 Bern, Switzerland.
3
Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland.
4
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.
5
Institute of Anatomy, University of Bern, Baltzerstrasse 2, CH-3012 Bern, Switzerland.
6
Institute of Cell Biology, University of Bern, Baltzerstrasse 4, CH-3012 Bern, Switzerland. Electronic address: smita.saxena@izb.unibe.ch.

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.

PMID:
26748090
DOI:
10.1016/j.neuron.2015.11.033
[Indexed for MEDLINE]
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