Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms

作者：Gautam Mukesh; Jara Javier H; Sekerkova Gabriella; Yasvoina Marina V; Martina Marco; Oezdinler P Hande

来源：Human Molecular Genetics, 2016, 25(6): 1074-1087.

DOI：10.1093/hmg/ddv631

Mutations in the ALS2 gene result in early-onset amyotrophic lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia and juvenile primary lateral sclerosis, suggesting prominent upper motor neuron involvement. However, the importance of alsin function for corticospinalmotor neuron (CSMN) health and stability remains unknown. To date, four separate alsin knockout (Alsin(KO)) mousemodels have been generated, and despite hopes ofmimicking human pathology, none displayed profound motor function defects. This, however, does not rule out the possibility of neuronal defects within CSMN, which is not easy to detect in thesemice. Detailed cellular analysis of CSMNhas been hampered due to their limited numbers and the complex and heterogeneous structure of the cerebral cortex. In an effort to visualize CSMN in vivo and to investigate precise aspects of neuronal abnormalities in the absence of alsin function, we generated Alsin(KO)-UeGFP mice, by crossing Alsin(KO) and UCHL1-eGFP mice, a CSMN reporter line. We find that CSMN display vacuolated apical dendrites with increased autophagy, shrinkage of soma size and axonal pathology even in the pons region. Immunocytochemistry coupled with electron microscopy reveal that alsin is important for maintaining cellular cytoarchitecture and integrity of cellular organelles. In its absence, CSMN displays selective defects both in mitochondria and Golgi apparatus. UCHL1-eGFP mice help understand the underlying cellular factors that lead to CSMN vulnerability in diseases, and our findings reveal unique importance of alsin function for CSMN health and stability.

• 出版日期2016-3-15
• 单位西北大学