Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy
Abstract Autosomal dominant missense mutations in BICD2 cause Spinal Muscular Atrophy Lower Extremity Predominant 2 (SMALED2), a developmental disease of motor neurons. BICD2 is a key component of the cytoplasmic dynein/dynactin motor complex, which in axons drives the microtubule-dependent retrogra...
| المؤلفون الرئيسيون: | , , , , , , |
|---|---|
| التنسيق: | مقال |
| اللغة: | English |
| منشور في: |
BMC
2020-03-01
|
| سلاسل: | Acta Neuropathologica Communications |
| الموضوعات: | |
| الوصول للمادة أونلاين: | http://link.springer.com/article/10.1186/s40478-020-00909-6 |
| _version_ | 1828857897046507520 |
|---|---|
| author | Alexander M. Rossor James N. Sleigh Michael Groves Francesco Muntoni Mary M. Reilly Casper C. Hoogenraad Giampietro Schiavo |
| author_facet | Alexander M. Rossor James N. Sleigh Michael Groves Francesco Muntoni Mary M. Reilly Casper C. Hoogenraad Giampietro Schiavo |
| author_sort | Alexander M. Rossor |
| collection | DOAJ |
| description | Abstract Autosomal dominant missense mutations in BICD2 cause Spinal Muscular Atrophy Lower Extremity Predominant 2 (SMALED2), a developmental disease of motor neurons. BICD2 is a key component of the cytoplasmic dynein/dynactin motor complex, which in axons drives the microtubule-dependent retrograde transport of intracellular cargo towards the cell soma. Patients with pathological mutations in BICD2 develop malformations of cortical and cerebellar development similar to Bicd2 knockout (−/−) mice. In this study we sought to re-examine the motor neuron phenotype of conditional Bicd2 −/− mice. Bicd2 −/− mice show a significant reduction in the number of large calibre motor neurons of the L4 ventral root compared to wild type mice. Muscle-specific knockout of Bicd2 results in a similar reduction in L4 ventral axons comparable to global Bicd2 −/− mice. Rab6, a small GTPase required for the sorting of exocytic vesicles from the Trans Golgi Network to the plasma membrane is a major binding partner of BICD2. We therefore examined the secretory pathway in SMALED2 patient fibroblasts and demonstrated that BICD2 is required for physiological flow of constitutive secretory cargoes from the Trans Golgi Network to the plasma membrane using a VSV-G reporter assay. Together, these data indicate that BICD2 loss from muscles is a major driver of non-cell autonomous pathology in the motor nervous system, which has important implications for future therapeutic approaches in SMALED2. |
| first_indexed | 2024-12-13T01:45:50Z |
| format | Article |
| id | doaj.art-04ee3d3f84b74b1fb66a3c8f9d0120f1 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-13T01:45:50Z |
| publishDate | 2020-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-04ee3d3f84b74b1fb66a3c8f9d0120f12022-12-22T00:03:38ZengBMCActa Neuropathologica Communications2051-59602020-03-018111210.1186/s40478-020-00909-6Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophyAlexander M. Rossor0James N. Sleigh1Michael Groves2Francesco Muntoni3Mary M. Reilly4Casper C. Hoogenraad5Giampietro Schiavo6UCL Queen Square Institute of Neurology, University College LondonUCL Queen Square Institute of Neurology, University College LondonUCL Queen Square Institute of Neurology, University College LondonDubowitz Neuromuscular Centre and National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London Institute of Child HealthUCL Queen Square Institute of Neurology, University College LondonCell Biology, Neurobiology and Biophysics, Department of Biology, Utrecht UniversityUCL Queen Square Institute of Neurology, University College LondonAbstract Autosomal dominant missense mutations in BICD2 cause Spinal Muscular Atrophy Lower Extremity Predominant 2 (SMALED2), a developmental disease of motor neurons. BICD2 is a key component of the cytoplasmic dynein/dynactin motor complex, which in axons drives the microtubule-dependent retrograde transport of intracellular cargo towards the cell soma. Patients with pathological mutations in BICD2 develop malformations of cortical and cerebellar development similar to Bicd2 knockout (−/−) mice. In this study we sought to re-examine the motor neuron phenotype of conditional Bicd2 −/− mice. Bicd2 −/− mice show a significant reduction in the number of large calibre motor neurons of the L4 ventral root compared to wild type mice. Muscle-specific knockout of Bicd2 results in a similar reduction in L4 ventral axons comparable to global Bicd2 −/− mice. Rab6, a small GTPase required for the sorting of exocytic vesicles from the Trans Golgi Network to the plasma membrane is a major binding partner of BICD2. We therefore examined the secretory pathway in SMALED2 patient fibroblasts and demonstrated that BICD2 is required for physiological flow of constitutive secretory cargoes from the Trans Golgi Network to the plasma membrane using a VSV-G reporter assay. Together, these data indicate that BICD2 loss from muscles is a major driver of non-cell autonomous pathology in the motor nervous system, which has important implications for future therapeutic approaches in SMALED2.http://link.springer.com/article/10.1186/s40478-020-00909-6Spinal muscular atrophySMALED2Hereditary motor neuropathyBICD2DYNC1H1Muscle |
| spellingShingle | Alexander M. Rossor James N. Sleigh Michael Groves Francesco Muntoni Mary M. Reilly Casper C. Hoogenraad Giampietro Schiavo Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy Acta Neuropathologica Communications Spinal muscular atrophy SMALED2 Hereditary motor neuropathy BICD2 DYNC1H1 Muscle |
| title | Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy |
| title_full | Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy |
| title_fullStr | Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy |
| title_full_unstemmed | Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy |
| title_short | Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy |
| title_sort | loss of bicd2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy |
| topic | Spinal muscular atrophy SMALED2 Hereditary motor neuropathy BICD2 DYNC1H1 Muscle |
| url | http://link.springer.com/article/10.1186/s40478-020-00909-6 |
| work_keys_str_mv | AT alexandermrossor lossofbicd2inmuscledrivesmotorneuronlossinadevelopmentalformofspinalmuscularatrophy AT jamesnsleigh lossofbicd2inmuscledrivesmotorneuronlossinadevelopmentalformofspinalmuscularatrophy AT michaelgroves lossofbicd2inmuscledrivesmotorneuronlossinadevelopmentalformofspinalmuscularatrophy AT francescomuntoni lossofbicd2inmuscledrivesmotorneuronlossinadevelopmentalformofspinalmuscularatrophy AT marymreilly lossofbicd2inmuscledrivesmotorneuronlossinadevelopmentalformofspinalmuscularatrophy AT casperchoogenraad lossofbicd2inmuscledrivesmotorneuronlossinadevelopmentalformofspinalmuscularatrophy AT giampietroschiavo lossofbicd2inmuscledrivesmotorneuronlossinadevelopmentalformofspinalmuscularatrophy |