PT  - JOURNAL ARTICLE
AU  - Melanie V. Halbach
AU  - Nesli-Ece Sen
AU  - Júlia Canet-Pons
AU  - Bram W. Kuppens
AU  - Mandy Segers
AU  - Martijn Schonewille
AU  - Ewa Rollmann
AU  - Kay Seidel
AU  - Udo Rüb
AU  - David Meierhofer
AU  - Michel Mittelbronn
AU  - Patrick Harter
AU  - Chris I. De Zeeuw
AU  - Luis E. Almaguer-Mederos
AU  - Suzana Gispert
AU  - Laurens W.J. Bosman
AU  - Georg Auburger
TI  - <em>Atxn2</em>-CAG100-knock-in affects mouse lifespan and vestibulo-cerebellar function via neural disconnection
AID  - 10.1101/333443
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 333443
4099  - http://biorxiv.org/content/early/2018/06/04/333443.short
4100  - http://biorxiv.org/content/early/2018/06/04/333443.full
AB  - Unstable expansions in the Q22-polyglutamine domain of human ATXN2 mediate risks for motor neuron diseases such as ALS/FTLD or cause the autosomal dominant Spinocerebellar Ataxia type 2 (SCA2), but the pathogenesis is not understood and models are unavailable.We generated a novel knock-in mouse line with CAG100 expansion in Atxn2, transmitted unstably. The mutant protein accumulated in neuronal cytosolic aggregates, with a characteristic pattern of multi-system-atrophy. Loss-of-function phenotypes included less mutant offspring, initial weight gain and motor hyperactivity. Progressive toxic aggregation effects started around 20 weeks in homozygous animals showing weight loss, reduced muscle strength and gait ataxia. Lifespan was decreased. In the cerebellum, neuronal soma and dendrites were remarkably spared. However, myelin proteins MBP, CNP, PLP1 and transcripts Mal, Mobp, Rtn4 decreased markedly, especially adhesion factors MAG and MOG. In neurons, strong reductions were found for mRNAs of perineuronal elements Haplnl, Hapln2, Hapln4, of axonal myelin interactors Prnp and Klk6. At protein level, the adhesion factor neuroplastin and neurofilaments were strongly reduced, while presynaptic alpha-synuclein increased two-fold.Overall, this authentic SCA2 mouse model elucidates how altered function and aggregation toxicity of ATXN2 conspire to trigger axon-myelin disconnection. This model will promote the development of neuroprotective therapies and disease biomarkers.