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김현태Hyuntae Kim

University Hospital Bonn

Brain, Mar 13 2024, awae081 | https://doi.org/10.1093/brain/awae081 Paroxysmal dystonia results from the loss of RIM4 in Purkinje cells

Hyuntae Kim,¹ Nesrine Melliti,² Eva Breithausen,² Katrin Michel,² Sara Ferrando Colomer,¹ Ekaterina Poguzhelskaya,¹ Paulina Nemcova,¹ Laura Ewell,³Sandra Blaess,⁴ Albert Becker,²Julika Pitsch,⁵ Dirk Dietrich^1,† and Susanne Schoch^2,†

¹Synaptic Neuroscience Team, Department of Neurosurgery, University Hospital Bonn, 53105 Bonn, Germany

²Synaptic Neuroscience Team, Institute of Neuropathology, University Hospital Bonn, 53105 Bonn, Germany

³School of Medicine, UC Irvine, 92697 Irvine, USA

⁴Institute of Reconstructive Neurobiology, University Hospital Bonn, 53105 Bonn, Germany

⁵Department of Epileptology, University Hospital Bonn, 53105 Bonn, Germany

^†These authors contributed equally to this work.

Correspondence to: Susanne Schoch

Correspondence may also be addressed to: Dirk Dietrich

Abstract

Full-length RIM1 and 2 are key components of the presynaptic active zone that ubiquitously control excitatory and inhibitory neurotransmitter release. Here, we report that the function of the small RIM isoform RIM4, consisting of a single C2 domain, is strikingly different from that of the long isoforms. RIM4 is dispensable for neurotransmitter release but plays a postsynaptic, cell-type specific role in cerebellar Purkinje cells that is essential for normal motor function. In the absence of RIM4, Purkinje cell intrinsic firing is reduced and caffeine-sensitive, and dendritic integration of climbing fibre input is disturbed. Mice lacking RIM4, but not mice lacking RIM1/2, selectively in Purkinje cells exhibit a severe, hours-long paroxysmal dystonia. These episodes can also be induced by caffeine, ethanol or stress and closely resemble the deficits seen with mutations of the PNKD (paroxysmal non-kinesigenic dystonia) gene. Our data reveal essential postsynaptic functions of RIM proteins and show non-overlapping specialized functions of a small isoform despite high homology to a single domain in the full-length proteins.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-03-19)
연구진국외 연구진
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