title: Autophagy dysregulation in cell culture and animals models of spinal muscular atrophy.
abstract: Abnormal autophagy has become a central thread linking neurodegenerative diseases, particularly of the motor neuron. One such disease is spinal muscular atrophy (SMA), a genetic neuromuscular disorder caused by mutations in the SMN1 gene resulting in low levels of Survival Motor Neuron (SMN) protein. Despite knowing the causal protein, the exact intracellular processes that are involved in the selective loss of motor neurons remain unclear. Autophagy induction can be helpful or harmful depending on the situation, and we sought to understand the state of the autophagic response in SMA. We show that cell culture and animal models demonstrate induction of autophagy accompanied by attenuated autophagic flux, resulting in the accumulation of autophagosomes and their associated cargo. Expression of the SMN-binding protein a-COP, a known modulator of autophagic flux, can ameliorate this autophagic traffic jam.
authors.affiliation: Indiana University School of Medicine, Department of Dermatology, Walther Hall, R3 C636, Indianapolis, IN 46202, United States.
authors.forename: Sara K
authors.initials: SK
authors.lastname: Custer
authors.affiliation: Indiana University School of Medicine, Department of Dermatology, Walther Hall, R3 C636, Indianapolis, IN 46202, United States. Electronic address: eandro@iu.edu.
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Androphy
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009046:Motor Neurons / Q000502:physiology; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D000097573:Red Fluorescent Protein
chemical_list: D004318:Doxycycline; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D055533:Survival of Motor Neuron 1 Protein; D000097573:Red Fluorescent Protein; C480860:Map1lc3b protein, mouse
keywords: Autophagy; Motor neuron; Spinal muscular atrophy; Survival motor neuron