title: Non-aggregating tau phosphorylation by cyclin-dependent kinase 5 contributes to motor neuron degeneration in spinal muscular atrophy.
abstract: Mechanisms underlying motor neuron degeneration in spinal muscular atrophy (SMA), the leading inherited cause of infant mortality, remain largely unknown. Many studies have established the importance of hyperphosphorylation of the microtubule-associated protein tau in various neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. However, tau phosphorylation in SMA pathogenesis has yet to be investigated. Here we show that tau phosphorylation on serine 202 (S202) and threonine 205 (T205) is increased significantly in SMA motor neurons using two SMA mouse models and human SMA patient spinal cord samples. Interestingly, phosphorylated tau does not form aggregates in motor neurons or neuromuscular junctions (NMJs), even at late stages of SMA disease, distinguishing it from other tauopathies. Hyperphosphorylation of tau on S202 and T205 is mediated by cyclin-dependent kinase 5 (Cdk5) in SMA disease condition, because tau phosphorylation at these sites is significantly reduced in Cdk5 knock-out mice; genetic knock-out of Cdk5 activating subunit p35 in an SMA mouse model also leads to reduced tau phosphorylation on S202 and T205 in the SMA;p35(-/-) compound mutant mice. In addition, expression of the phosphorylation-deficient tauS202A,T205A mutant alleviates motor neuron defects in a zebrafish SMA model in vivo and mouse motor neuron degeneration in culture, whereas expression of phosphorylation-mimetic tauS202E,T205E promotes motor neuron defects. More importantly, genetic knock-out of tau in SMA mice rescues synapse stripping on motor neurons, NMJ denervation, and motor neuron degeneration in vivo. Altogether, our findings suggest a novel mechanism for SMA pathogenesis in which hyperphosphorylation of non-aggregating tau by Cdk5 contributes to motor neuron degeneration.
authors: Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611.
authors: Nimrod
authors: N
authors: Miller
authors: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089.
authors: Zhihua
authors: Z
authors: Feng
authors: Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611.
authors: Brittany M
authors: BM
authors: Edens
authors: Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611.
authors: Ben
authors: B
authors: Yang
authors: Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611.
authors: Han
authors: H
authors: Shi
authors: Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611.
authors: Christie C
authors: CC
authors: Sze
authors: Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
authors: Benjamin Taige
authors: BT
authors: Hong
authors: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and.
authors: Susan C
authors: SC
authors: Su
authors: Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611.
authors: Jorge A
authors: http://orcid.org/0000-0002-8881-2649
authors: JA
authors: Cantu
authors: Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611.
authors: Jacek
authors: J
authors: Topczewski
authors: Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors: Thomas O
authors: TO
authors: Crawford
authors: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089.
authors: Chien-Ping
authors: CP
authors: Ko
authors: Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors: Charlotte J
authors: http://orcid.org/0000-0001-5088-6012
authors: CJ
authors: Sumner
authors: State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
authors: Long
authors: L
authors: Ma
authors: Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611, ma@northwestern.edu.
authors: Yong-Chao
authors: http://orcid.org/0000-0002-2469-4356
authors: YC
authors: Ma
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D018482:Muscle, Skeletal / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000150:complications / Q000235:genetics / Q000473:pathology; D009410:Nerve Degeneration / Q000209:etiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation; D012097:Repressor Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish; D016875:tau Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C000624101:Cux1 protein, mouse; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D012097:Repressor Proteins; D055533:Survival of Motor Neuron 1 Protein; C485184:enhanced green fluorescent protein; D016875:tau Proteins; D049452:Green Fluorescent Proteins; D051360:Cyclin-Dependent Kinase 5
keywords: Cdk5; SMA; motor neuron; neurodegeneration; tau