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Hum Mol Genet. 2018 May 15;27(10):1772-1784. doi: 10.1093/hmg/ddy086.

Novel insights into SMALED2: BICD2 mutations increase microtubule stability and cause defects in axonal and NMJ development.

Author information

1
Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
2
Institute for Genetics, University of Cologne, 50674 Cologne, Germany.
3
Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
4
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
5
Center for Rare Diseases Cologne, University Hospital of Cologne, 50931 Cologne, Germany.

Abstract

Bicaudal D2 (BICD2) encodes a highly conserved motor adaptor protein that regulates the dynein-dynactin complex in different cellular processes. Heterozygous mutations in BICD2 cause autosomal dominant lower extremity-predominant spinal muscular atrophy-2 (SMALED2). Although, various BICD2 mutations have been shown to alter interactions with different binding partners or the integrity of the Golgi apparatus, the specific pathological effects of BICD2 mutations underlying SMALED2 remain elusive. Here, we show that the fibroblasts derived from individuals with SMALED2 exhibit stable microtubules. Importantly, this effect was observed regardless of where the BICD2 mutation is located, which unifies the most likely cellular mechanism affecting microtubules. Significantly, overexpression of SMALED2-causing BICD2 mutations in the disease-relevant cell type, motor neurons, also results in an increased microtubule stability which is accompanied by axonal aberrations such as collateral branching and overgrowth. To study the pathological consequences of BICD2 mutations in vivo, and to address the controversial debate whether two of these mutations are neuron or muscle specific, we generated the first Drosophila model of SMALED2. Strikingly, neuron-specific expression of BICD2 mutants resulted in reduced neuromuscular junction size in larvae and impaired locomotion of adult flies. In contrast, expressing BICD2 mutations in muscles had no obvious effect on motor function, supporting a primarily neurological etiology of the disease. Thus, our findings contribute to the better understanding of SMALED2 pathology by providing evidence for a common pathomechanism of BICD2 mutations that increase microtubule stability in motor neurons leading to increased axonal branching and to impaired neuromuscular junction development.

PMID:
29528393
DOI:
10.1093/hmg/ddy086

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