Volume Articles

Commentary: engrailed 1 shapes the dopaminergic and serotonergic landscape through proper Iso maintenance and function

Willemieke M. Kouwenhoven and Marten P. Smidt*

 Two essential monoaminergic neurotransmitter systems are located within the midbrain and the hindbrain region: the mesodiencephalic dopaminergic (mdDA) neurons, which can be divided in the substantia nigra (SN), the ventral tegmental area (VTA), and the serotonergic (5-HT) neurons. In the adult brain these two types of monoaminergic neurons are critical to our neurological health. Dysfunction of the mdDA system has been associated with schizophrenia and Parkinson's Disease (PD), while dysfunction of the 5HT system has in turn been associated with psychiatric diseases such as depression and autism. The homeobox transcription factor Engrailed 1 (En1) is expressed in both types monoaminergic neurons, and is required for the correct programming and survival of the mdDA and 5HT neurons. Recently, we reported on the dual role of En1 in both neurotransmitter systems through its central role in the maintenance of the Isthmic Organizer, which is the embryonic signaling center that instructs and separates dopaminergic and serotonergic neuronal development.

The Roles of Lysosomal Exocytosis in Regulated Myelination

Yun-Tian Shen¹, Ying Yuan^1,2, Wen-Feng Su¹, Yun Gu¹, Gang Chen^1*

 The myelin sheath wraps axons is an intricate process required for rapid conduction of nerve impulses, which is formed by two kinds of glial cells, oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. Myelin biogenesis is a complex and finely regulated process and accumulating evidence suggests that myelin protein synthesis, storage and transportation are key elements of myelination, however the mechanisms of regulating myelin protein trafficking are still not very clear. Recently, the evidences of lysosomal exocytosis in oligodendrocytes and Schwann cells are involved in regulated myelination have emerged. In this paper, we briefly summarize how the major myelin-resident protein, as proteolipid protein in the central nervous system and P0 in the peripheral nervous system, transport from lysosome to cell surface to form myelin sheath and focus on the possible mechanisms involved in these processes. Advances in our understanding of glia, as well as new tools engineering, will further improve the knowing of myelin biogenesis.

Clinical role of a subcortical communication

Esther A. Pelzer^1,2*, Lars Timmermann², Marc Tittgemeyer¹

 Subcortical communication is an important underlying feature for the smooth performance of motor behaviour. Especially movement disorders like Parkinson’s disease show impairment in the basal-ganglio-thalamic and cerebello-thalamic communication; but also an impairment of the direct communication between these two structures has been proposed.

In this review we highlight important clinical findings concerning the pathological communication between these subcortical structures; additionally we propose a new hypothesis in the development of neurodegenerative disease: we assume that axon degeneration is crucially implicated in the development of parkinsonian symptoms and link the current findings to the development of pathological oscillatory activity. New techniques like probabilistic tractography now offer the possibility to in vivo measure axon degeneration by the determination of connectivity decline and allow the combination with electrophysiological recording. We hypothesize that a change in frequency bands in oscillatory activity might be a product of underlying axonal degeneration; moreover axonal degeneration might be worsened by pathological oscillatory activity resulting in a vicious circle. The thalamus, as main relay station between the basal ganglia and the cerebellum seems to be involved in this disease pathology in Parkinson’s disease.

EGF and the potassium channel Kv1.3 are promising pharmacological targets against neuro-degenerative diseases

Ramón Martínez-Mármol¹, Mercè Salla-Martret², Daniel Sastre², Irene Estadella², Antonio Felipe^2*

 The adult mammalian brain contains neural stem cells (NSCs) that generate neurons and glial cells throughout the lifetime of an organism. NSCs reside in at least two germinal epithelium regions of the adult brain, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone of the hippocampus. Newborn neurons incorporate into the existing functional networks and play important innate and adaptive roles in cognition, behavior and tissue repair1,2. The identity of particular neural stem cells that generate different classes of neurons and glia, as well as the molecular mechanisms that governs this process in vivo, is a subject of extensive research and debate. Epidermal Growth Factor Receptor (EGFR) activation is one of the most important pathways controlling neural stem cell number and self-renewal3,4. On the other hand, the Shaker-type delayed rectifier K+ channel Kv1.3 functions during cell proliferation, differentiation and migration in many cell types5. This channel is expressed in brain progenitor cells where participates in modulating their final fate. This review summarizes the major findings concerning Kv1.3 and neural stem cell modulation, emphasizing the combination of Kv1.3 with EGFR as promising pharmacological targets against autoimmune neuro-degenerative diseases.

Exercise-induced changes in basal ganglia volume and their relation to cognitive performance

Becker L¹, Kutz DF², Voelcker-Rehage C^1*

Tyrosyl-DNA Phosphodiesterase I a critical survival factor for neuronal development and homeostasis

Robert C.A.M. van Waardenburg*

 Tyrosyl-DNA phosphodiesterase I (TDP1), like most DNA repair associated proteins, is not essential for cell viability. However, dysfunctioning TDP1 or ATM (ataxia telangiectasia mutated) results in autosomal recessive neuropathology with similar phenotypes, including cerebellar atrophy. Dual inactivation of TDP1 and ATM causes synthetic lethality. A TDP1H493R catalytic mutant is associated with spinocerebellar ataxia with axonal neuropathy (SCAN1), and stabilizes the TDP1 catalytic obligatory enzyme-DNA covalent complex. The ATM kinase activates proteins early on in response to DNA damage. Tdp1-/- and Atm-/- mice exhibit accumulation of DNA topoisomerase I-DNA covalent complexes (TOPO1-cc) explicitly in neuronal tissue during development. TDP1 resolves 3’- and 5’-DNA adducts including trapped TOPO1-cc and TOPO1 protease resistant peptide-DNA complex. ATM appears to regulate the response to TOPO1-cc via a noncanonical function by regulating SUMO/ubiquitin-mediated TOPO1 degradation. In conclusion, TDP1 and ATM are critical factors for neuronal cell viability via two independent but cooperative pathways.

Mini review - Clinical and physiological aspects of pain in parkinson's disease

Eduardo NC Bergamaschi¹, Fernanda C Nunes^2,3, Victor W de Oliveira³, Alessandra Laitart³, Maria L Benevides³, Jean C Nunes^2,3*

 Pain is a common and often disabling symptom in Parkinson’s disease (PD) which has received increasing attention in recent years. Headache represents a common form of pain among the general population, but there are few studies on this symptom in PD. In 2014, our group reported a lower prevalence of headache in PD patients compared to the general population, as well as an association between the predominant side of headache and the side of initial motor signs of PD. Since then, there has been few new data on the specific issue of headache in PD patients, though several recent studies have contributed to the understanding of pain in PD, both in terms of clinical and pathophysiological aspects, including new observations on pain association with side of motor symptom onset. Here, we review those studies, and re-discuss our own findings in comparison to the current information available. A better comprehension of pain physiology in PD could facilitate the development of new therapeutic approaches, thus providing a better quality of life for PD patients.

Lung inflammation regulates autoimmunity in the central nervous system

Masashi Kanayama¹, Mari L. Shinohara^2*

 Abstract Autoimmune diseases of the central nervous system (CNS), such as multiple sclerosis (MS), are characterized by infiltration of pathogenic immune cells in the CNS. Cells infiltrated in the CNS express pro-inflammatory molecules and cause demyelination. The direct impact of lung immune responses was not previously considered in the pathogenesis of CNS inflammation. However, it recently became clear that the lung acts as a hub organ of pathogenic T cells that are migrating to the CNS. More recent studies further showed that inflamed lung has a critical impact on autoimmune CNS inflammation. Here, we discuss the contribution of the lung in the pathogenesis of CNS autoimmune diseases based on recent reports.