Special Issue "Studies of Motor Molecules"

Guest Editor
Prof. Dr. Catherine Krull
Biologic and Materials Sciences, University of Michigan, 5211 Dental, 1011 N. University Ave., Ann Arbor, MI 48109, USA
Website: http://www.dent.umich.edu/?q=bms/facultyandstaff/krull
E-Mail: krullc@umich.edu
Phone: +1 734 764-5441

Dear Colleagues,

The advent of discussing motor molecules has made this special issue possible; not only WHAT they do but HOW they do it, whether it is forming specific groups of motor neurons or axon pathfinding. We will get down to the nitty-gritty, so to say, and figure out how these motor molecules influence other signaling molecules in the cell or the cytoskeleton. Using many animal models, we have assembled this special issue that focuses on the use of motor molecules. Perhaps most importantly, we will also focus on diseases of motor neurons and their axons. Overall, we expect this special issue on motor molecules to develop your critical insights into this important problem: how molecules are used to form groupings of motor neurons and how molecules influence axons of motor neurons as they are guided to their target regions!

Prof. Dr. Catherine Krull
Guest Editor

Submission

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• motor neurons
• molecular cues
• axons
• animal models
• neurological disease
• imaging

Type of Paper: Review
Title: Crossing the Border: Molecular Control of Motor Axon Exit
Authors: Arlene Bravo ¹ and Zaven Kaprielian ^1,2
Affiliations: ¹ Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
E-Mail: arlene.bravo@med.einstein.yu.edu
² Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; E-Mail: zaven.kaprielian@einstein.yu.edu
Abstract: Living organisms rely heavily on the function of motor circuits for their survival and in order to adapt to their ever-changing environments. Unique among all other classes of central nervous system (CNS) neurons, motor neurons (MNs) project their axons out of the CNS. Once in the periphery motor axons navigate along highly stereotyped trajectories, often at considerable distances from their cell bodies, to innervate appropriate muscle targets. A key decision made by pathinding motor axons is whether to exit the CNS through dorsal or ventral motor axon exit points (MEPs). In contrast to the major advances made in understanding the mechanisms that regulate the specification of MN subtypes and the innervation of limb muscles, remarkably little is known about how MN axons project out of the CNS. Nevertheless, a limited number of studies, mainly in Drosophila, have identified transcription factors, and in some cases candidate downstream effector molecules, that are required for motor axons to exit the spinal cord. Notably, specialized neural crest cell derivatives, referred to as Boundary Cap (BC) cells, pre-figure and demarcate MEPs in vertebrates. Surprisingly, however, BC cells are not required for MN axon exit, but rather prevent MN cell bodies from ectopically migrating along their axons out of the CNS. Here, we highlight findings from Drosophila and vertebrates that reveal our fragmentary knowledge of the mechanisms that guide motor axons out of the CNS.

Type of Paper: Article
Title: Defect of Axonal Transport in Motor Neuron Diseases
Authors: Masahisa Katsuno, Kensuke Ikenaka, Shinsuke Ishigaki, Fumiaki Tanaka and Gen Sobue
Affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan;
E-Mails: ka2no@med.nagoya-u.ac.jp (M.S.); sobueg@med.nagoya-u.ac.jp (G.S.)
Abstract: Motor neurons are morphologically characterized by a long axon that protrudes from the cell body, and fine tuning of axonal transport is crucial for their survival. Obstruction of axonal transport is gaining attention as a cause of neuronal dysfunction in a variety of neurodegenerative diseases that affect motor neurons. Depletion of motor molecules regulating axonal trafficking, dynein and dynactin 1, is shown to disrupt axonal transport in flies, whereas mutations in the genes encoding these molecules cause motor neuron degeneration in both humans and rodents. Defected axonal transport is among the early molecular events in the pathogenesis of neurodegeneration in the mouse models of amyotrophic lateral sclerosis (ALS). Gene expression profiles using microarray technology combined with laser-captured microdissection shows that the expression of dynactin 1 is down-regulated in the degenerating spinal motor neurons isolated from autopsied patients with sporadic ALS. The mRNA level of dynactin 1 is also reduced in the affected neurons of a mouse model of spinal and bulbar muscular atrophy (SBMA), a motor neuron disease caused by triplet CAG repeat expansion in the gene coding androgen receptor (AR). Pathogenic AR proteins also activate c-Jun N-terminal kinase (JNK), leading to inhibition of kinesin-1 microtubule-binding activity and eventual disruption of anterograde axonal transport. Nevertheless, there are several studies that deny the direct role of motor molecules in the pathogenesis of motor neuron diseases. These observations suggest that the relationship between axonal transport and motor neuron degeneration needs to be further investigated to elucidate the molecular mechanism underlying motor neuron damage.

Type of Article: Review
Title: The Wnt and BMP Families of Signaling Morphogens at the Vertebrate Neuromuscular Junction
Authors: Juan P. Henríquez ¹ , Catherine E. Krull ² and Nelson Osses ³
Affiliations: ¹ Laboratory of Developmental Neurobiology, Faculty of Biological Sciences, University of Concepcion, Chile; E-Mail: jhenriquez@udec.cl
² Department of Biologic and Materials Science, University of Michigan Medical School, Ann Arbor, Michigan, MI, USA; E-Mail: krullc@umich.edu
³ Institute of Chemistry, Faculty of Sciences, P. Catholic University of Valparaiso, Chile
Abstract: The neuromuscular junction (NMJ) has been extensively employed to identify crucial determinants of synaptogenesis. At the vertebrate NMJ, extracellular matrix and signaling proteins play stimulatory and inhibitory roles on the assembly of functional synapses. Studies in Drosophila have revealed crucial functions for early morphogens during the assembly and maturation of the NMJ. Here, we discuss growing evidence addressing the function of Wnt and BMP signaling pathways at the vertebrate NMJ. We focus on the emerging role of Wnt proteins as positive and negative regulators of postsynaptic differentiation. We also address the possible involvement of BMP pathways on motor neuron behaviour for NMJ assembly and/or regeneration.

Type of Paper: Review
Title: Molecular Motor Proteins and Amyotrophic Lateral Sclerosis
Authors: Kai Y. Soo, Manal Farg and Julie D. Atkin
Affiliations: Department of Biochemistry, La Trobe Institute of Molecular Science, La Trobe University, VIC 3086, Australia; E-Mail: j.atkin@latrobe.edu.au
Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons in the brain, brainstem and spinal cord, which is characterized by motor dysfunction, muscle dystrophy and progressive paralysis. Both inherited and sporadic forms of ALS share common pathological features, however, the initial trigger of neurodegeneration remains unknown. Motor neurons are uniquely targeted by ubiquitously expressed proteins in ALS but the reason for this selectively vulnerability is unclear. However motor neurons have unique characteristics such as very long axons, large cell bodies and high energetic metabolism, therefore placing high demands on cellular transport processes. Defects in cellular trafficking are now widely reported in ALS, including dysfunction to the molecular motors dynein and kinesin. Abnormalities to dynein in particular are linked to ALS, and defects in dynein-mediated axonal transport processes have been reported as one of the earliest pathologies.  Furthermore, dynein is very highly expressed in neurons and neurons are particularly sensitive to dynein dysfunction.  Hence, unravelling cellular transport processes mediated by molecular motor proteins may help shed light on motor neuron loss in ALS.

Type of Paper: Review
Title: Uncontrollable Protein Misdirection Inside and Outside Motor Neurons in ALS: A Possible Clue for the Therapeutic Strategy
Author: Akemi Ido ^1,2, Hidenao Fukuyama ² and Makoto Urushitani ¹
Affiliation: ¹ Unit for Neurobiology and Therapeutics, Molecular Neuroscience Research Center, Shiga University of Medical Science, Shiga, Japan; E-Mail: uru@belle.shiga-med.ac.jp
² Human Brain Research Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive muscle wasting and weakness with no effective cure. Emerging evidence supports the notion that the abnormal conformation of ALS-linked proteins plays a central role in triggering the motor neuron degeneration. In particular, mutant types of superoxide dismutase 1 (SOD1) and TAR DNA binding protein 43kDa (TDP-43) are key molecules involved in the pathogenesis of familial and sporadic ALS, respectively. The commonalities of the two proteins include aggregate propensity and acquisition of the detrimental conformation through oligomerization, fragmentation or post-translational modification, which lead to the abnormal subcellular localization. Although SOD1 is a major cytosolic protein, mutation in SOD1 causes the aberrant distribution in mitochondria, endoplasmic reticulum, and even in the extracellular space. The nuclear exclusion of TDP-43 is a pathological hallmark for ALS, although the pathogenic priority remains elusive. Nevertheless, these abnormal behaviors based on the protein misfolding are believed to induce diverse intracellular and extracellular events, which may tightly link to non-cell-autonomous motor neuron death. The generation of mutant- or misfolded protein-specific antibody is efficient not only for uncovering the distribution and the propagation of the pathogenic proteins, but also for designing the therapeutic strategy to clear such species. We here reviewed the previous articles regarding the mislocalization of ALS-linked proteins, especially in mutant SOD1 and TDP-43, and discussed the rationale of immunotherapy against ALS-linked misfolded proteins.

Title: Localizations of Axonal Transport Components in Neurodegenerative Disorders
Author: Fulvio Florenzano
Affiliation: Confocal Microscopy Unit, EBRI and S. Lucia Foundation; Via Fosso del Fiorano, 64/65 - 00143 Rome, Italy; E-Mail: florenza@hsantalucia.it
Abstract: Axonal transport and neuronal survival depend critically on axon integrity for supplying proteins and organelles to different cellular domains. All these actions are executed through the motor molecules machinery which comprises cytoskeleton, transport and regulatory elements and that appear to be disrupted in neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Huntington's, Parkinson's and Alzheimer's disease. Many evidences have been provided that alterations in the motor molecules machinery provoke impaired organelles and vesicles motility, defects in synthetic and degradative pathways, impaired neurotrophic signaling, and accumulation of cellular products. These alterations appear to be especially relevant in projection and motor neurons, which have long axons to reach the farthest nerve endings, and that very often are primarily involved during neurodegenerative diseases. A growing body of literature indicates the presence of alterations to the motor molecules machinery, not only in expression levels and phosphorylations, but also in their subcellular distribution. Particularly affected are the anatomical areas and the populations of neurons which are selectively involved in neurodegenerative diseases. The implications of this altered subcellular localization and how axon survival and neuronal death are affected still remains not understood, although several hypotheses have been proposed. Indeed, in some disorders such as Huntington disease and in several motor neuron diseases specific loss of the axonal transport appear to be a primary hallmark of the disorder, while in Parkinson's and Alzheimer's disease the role that defective transport may play is less clear. Animal models suggest that defects in axonal transport are sufficient to induce neurodegeneration, that aspects of axonal transport may be involved in some disease process or, in other cases, may be  a downstream consequence of disease progression. This review looks comparatively to axonal transport elements localization in some neurodegenerative disorders by asking what aspects may be essential for axon survival and neuronal death.

Type of Paper: review
Title: Axonal Dysfunction and Traffic Impairments in Charcot-Marie-Tooth Disease
Authors: Benoit J. Gentil ¹ and Laura Cooper ¹
Affiliation: Department of Neurology/Neurosurgery and Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4 Canada; E-Mail: benoit.gentil@mcgill.ca
Abstract: Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders. It comprises a group of diseases caused by mutations in genes involved in Schwann cells and neuronal homeostasis that affect the normal function of peripheral nerves. So far mutations in 33 genes have been identified causing either the demyelinating form (CMT1) or the axonal form (CMT2). Genes involving a large variety of unrelated functions may lead to the same phenotype when mutated. Our review will focus on the common link between genes causing axonal phenotypes like MFN2, KIF1B, Rab7, TRPV4, GARS, NEFL, HSPB1, MPZ, and HSPB8. If KIF1B, a molecular motor, is directly linked to axonal transport, the involvement of the other CMT2-causing genes in such a function is less obvious. However, the last years have seen a growing list of evidence demonstrating that intracellular trafficking and mitochondrial dynamics might be dysfunctional in CMT2, and these mechanisms might present a common link between dissimilar CMT2-causing genes. The involvement of impaired transport in the pathogenesis of other rare neurological diseases is also discussed.

Type of Paper: Review
Title: Chemokine Control of Motor Cortex Regeneration after Transplantation of ES Cell Derived Neural Stem/Progenitor Cells
Authors: Nagisa Arimitsu, Jun Shimizu, Naruyoshi Fujiwara, Toshio Hazama and Noboru Suzuki
Affiliation: Department of Immunology and Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan; E-Mail: n3suzuki@marianna-u.ac.jp
Abstract: Neural stem / progenitor cells transplantation has been expected as a possible therapeutic approach of various damages in the central nervous system (CNS). In order to achieve cells transplantation, it is important to understand the molecular mechanisms involved in proper neural differentiation and cell migration to damaged tissue. Recent investigations have revealed that chemokines may regulate the migration of transplanted cells. In this review, we discuss our findings of involvement of stromal derived factor 1 (SDF1, CXCL12) to the embryonic stem (ES) cell – derived  neural cells migration and repopulating in damaged area, and the relation of other chemokines such as monocyte chemotactic protein-1 (MCP1, CCL2).

Title: Fragment C of Tetanus Toxin: New Insights into its Neuronal Signalling Pathway
Authors: Ana C. Calvo ¹, Sara Oliván ¹, Raquel Manzano ¹, José Aguilera ² and Rosario Osta ¹
Affiliations: ¹ LAGENBIO, Facultad de Veterinaria-I3A, Aragonese Institute of Health Sciences (IACS), University of Zaragoza, Miguel Servet, 177. 50013 Zaragoza, Spain; E-Mail: osta@unizar.es
² Institute of Neurosciences, Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain
Abstract: The non-toxic carboxi-terminal fragment of tetanus toxin heavy chain (fragment C) can be transported retrogradely to the central nervous system and therefore it has been used as a valuable biological carrier of neurotrophic factors to ameliorate neurodegenerative processes. More recently, the neuroprotective properties of fragment C have been also described in vitro and in vivo, involving an activation of Akt kinase and extracellular signal regulated kinase (ERK) signaling cascades through neurotrophin tyrosine kinase (Trk) receptors. Although the precise mechanism of the molecular internalization of fragment C into neuronal cells remains unknown, fragment C could be internalized and translocated into the neuronal cytosol by a clathrin-mediated pathway, dependent on adaptor proteins such as dynamin and AP-2. In this review the origins, molecular properties and possible signaling pathways of fragment C are revised to understand the biochemical characteristics of its intracellular and synaptic transport.
Keywords: Adaptor protein; clathrin-mediated pathway; dynamin; fragment C; tetanus toxin; neurotrophin; Trk receptors