**Author details**

Uwe Ueberham\* and Thomas Arendt

\*Address all correspondence to: Uwe.Ueberham@medizin.uni-leipzig.de

Department for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute for Brain Research, University Leipzig, Leipzig, Germany

### **References**

**4.3. Motor neuron diseases**

92 Trends in Cell Signaling Pathways in Neuronal Fate Decision

As mentioned above, Smads are essentially controlling the plasticity of NMJ, the intra-axonal transport and affect axonal repair processes. Accordingly, selective motor neuron diseases exhibit disturbances of Smad signalling, e.g. spinal muscular atrophy, [234], spinal bulbar

ALS is a progressive neurodegenerative disease, which targets upper and lower motor neurons. In the primary motor cortex and the anterior horn of the spinal cord, motor neurons disappear and the pyramidal tract degenerates [236-238]. The remaining motor neurons exhibit inclusion bodies e.g. Bunina bodies, hyaline and skein-like inclusions. The pathological transactive response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) was shown to be the major disease protein in ALS. Recently, increased nuclear immunoreactivity for pSmad2,3 in motor neurons was reported from sporadic ALS patients in spinal cord [239]. Motor neurons, where a colocalization of TDP-43 and pSmad2,3 in skeine-like and round hyaline inclusions was detected [239], show reduced nuclear pSmad2,3 immunoreactivity [240]. Obviously a disruption of Smad signalling by Smad segregation, comparable to AD or several tauopathies, enhances the loss of motor neuron function. Smad4 seems actively involved in the control of motor function as targeted disruption of Smad4 demonstrates [132]. Probably, increased nuclear pSmad2,3 content in the remaining ALS motor neurons indicates an endogenously initiated approach to a functional improvement. Experiments with an ALS mouse model support this hypothesis, because TGFβ2 administration ameliorated the motor performance of the mice [241]. A reduction of TDP-43 containing aggregates by Smad2 overexpression confirms in vitro a protective role of activated Smad signalling in ALS [242]. In summary, initiation and/or progression of many neurological disorders are directly linked to altered Smad signalling, comprising cytoplasmic Smad aggregation/sequestration, and nuclear reduction, disruption of transcriptional machinery and stimulating proapoptotic signalling, therefore disturbing biological processes, which are essential for all phases of

This manuscript was supported by the Project BBZ09: 14494 (University Leipzig) and the AFI-

Department for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig

muscular atrophy [235] or amyotrophic lateral sclerosis (ALS).

nervous system development and homeostasis.

and Thomas Arendt

\*Address all correspondence to: Uwe.Ueberham@medizin.uni-leipzig.de

Institute for Brain Research, University Leipzig, Leipzig, Germany

**Acknowledgements**

Project 984 000-150.

**Author details**

Uwe Ueberham\*


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**Section 2**

**Wnt Signaling and Neuronal Fate Decision**

**Wnt Signaling and Neuronal Fate Decision**

**Chapter 4**

**Wnt Signaling Roles on the Structure and Function of the**

Wnts compromise a large family of secreted glycoproteins that have shown to be part of the signaling molecules that regulate several aspects of development such as axis formation and midbrain development [1, 2]. In mammals at least 19 Wnt members have been found. The interaction of a Wnt protein with members of the Frizzled (Fz) family of seven-pass trans‐ membrane cell-surface receptors triggers the activation of the Wnt signaling pathway [3-5]. In human and mice, 10 members of the Fz family have been identified. In addition, receptor-like tyrosine kinase (Ryk) and receptor tyrosine kinase-like orphan receptor (Ror2) have been identified as alternative Wnt receptors [6-8]. Different Wnt signaling cascades are activated downstream the Wnt receptors, identified as Wnt/β-catenin or canonical pathway, and βcatenin-independent or non-canonical pathways. The canonical pathway involves the tran‐ scription of Wnt target genes, while activation of non-canonical Wnt pathways may induce either an increase in intracellular calcium concentration or activation of the c-Jun-N-terminal

The Wnt pathway participates in the development of the central nervous system (CNS) and growing evidence indicate that Wnts also regulates the function of the adult nervous system [11, 12]. In fact, most of the key components including Wnts and Fz receptors are expressed in the adult brain [13, 14]. Wnt ligands have shown to regulate synaptic assembly as well synaptic plasticity and neurotransmission [15-20], and more recently it has also been involved in the

Deregulation of the Wnt signaling has been associated to several pathologies, been cancer the most widely documented [26-28]. More recently, altered Wnt signaling have been related to

> © 2013 Inestrosa and Varela-Nallar; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 Inestrosa and Varela-Nallar; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

mental disorders, mood disorders and neurodegenerative diseases [12, 29-32].

**Central Synapses: Involvement in Alzheimer's Disease**

Nibaldo C. Inestrosa and Lorena Varela-Nallar

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54606

kinase (JNK) cascade [3, 9, 10].

adult neurogenesis [21-25].

**1. Introduction**
