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

Ruegsegger, Céline; Stucki, David; Steiner, Silvio; Angliker, Nico; Radecke, Julika; Keller, Eva; Zuber, Benoît; Rüegg, Markus A; Saxena, Smita (2016). Impaired mTORC1-Dependent Expression of Homer-3 Influences SCA1 Pathophysiology. Neuron, 89(1), pp. 129-146. Cell Press 10.1016/j.neuron.2015.11.033

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
08 Faculty of Science > Department of Biology > Institute of Cell Biology
09 Interdisciplinary Units > Microscopy Imaging Center (MIC)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Ruegsegger, Céline; Stucki, David; Radecke, Julika; Zuber, Benoît and Saxena, Smita

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0896-6273

Publisher:

Cell Press

Language:

English

Submitter:

Benoît Zuber

Date Deposited:

28 Jan 2016 13:25

Last Modified:

14 Feb 2019 18:05

Publisher DOI:

10.1016/j.neuron.2015.11.033

PubMed ID:

26748090

BORIS DOI:

10.7892/boris.74781

URI:

https://boris.unibe.ch/id/eprint/74781

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