Volume Articles

Obesity and Multiple Sclerosis Susceptibility: A Review

Milena A. Gianfrancesco and Lisa F. Barcellos*

Several studies conducted around the world over the last decade have demonstrated that early childhood and adolescent obesity are significant risk factors for MS susceptibility. This association has been largely confirmed in females, while evidence supporting a strong role for obesity and risk of MS in males has been mixed. Further, interaction between increased body mass index and genetic as well as environmental factors in MS susceptibility has been proposed, and evidence of a causal relationship has recently been established. In this review, we discuss findings supporting the significant association between obesity and MS, as well as identify areas for future investigation.

Comment: New potential pharmacological functions of Chinese herbal medicines via regulation of autophagy: the search of reliable pharmaceutical candidates for chronic disorders therapy

Simon Wing Fai Mok, Vincent Kam Wai Wong, Betty Yuen Kwan Law*

Chronic diseases are the leading causes of physical impairments and mortality in the world. The functional role of autophagy in maintaining cellular homeostasis implies that the molecular machinery is a compelling pharmaceutical target for such disorders involving overall body imbalance. Therefore, autophagy modulators appeared to be the ideal source for hunting of novel and effective pharmaceutical interventions. Law et al., have performed a systematic review on more than 30 different Chinese herbal medicine (CHM)-derived bioactive compounds capable of regulating autophagy activity. The successful experimental and clinical applications of these compounds which have not been previously documented have been discussed. Notably, most of the reported novel applications are associated with chronic dysfunctions.

Managing post-traumatic trigeminal neuropathic pain: is surgery enough?

John R. Zuniga^1*, Tara F. Renton²

In the absence of effective non-surgical methods to permanently resolve neuropathic pain involving the lip, chin, or tongue following inferior alveolar and/or lingual nerve injury, microsurgery of these nerves has been a recommended modality. In two ambispective clinical trials, we demonstrated that phenotypic differences exist between individuals with neuropathic pain and those without neuropathic pain of the trigeminal nerve. In those without neuropathic pain before microsurgery there was a 2% incidence of neuropathic pain after microsurgery whereas there was a 67% incidence of neuropathic pain after microsurgery, some reporting an increase in pain levels, when neuropathic pain was present before microsurgery. The recurrence of neuropathic pain after trigeminal microsurgery is likely multifactorial and might not depend on factors that normally affect useful or functional sensory recovery in those who have no neuropathic pain. These results indicate that the understanding of post-traumatic trigeminal neuropathic pain is incomplete. Predictive outcomes of treatment will probably improve when the etiology is better defined to allow mechanistic or target-/site-specific treatment. Until then, non-surgical treatment for post-traumatic trigeminal neuropathic pain remains a safer option. Risk factors have been identified for patients developing chronic post -surgical pain due to post-traumatic neuropathy. These include psychological, medical, and age related factors. The best management may lie in preoperative screening and avoidance of elective surgery for high risk patients as the prevention of post-traumatic trigeminal neuropathic pain in the absence of effective medical or surgical interventions.

Cerebral Waste Accumulation and Glymphatic Clearance as Mechanisms of Human Neurological Diseases

Aaron Dadas^1,2 Jolewis Washington⁴, Damir Janigro^1,3*

The brain is a complex system that requires continual regulation of parenchymal pressure, osmolarity, and waste removal for optimal function; despite this, human brain lacks any obvious extension of lymphatic circulation for moderating fluid and waste regulation. We recapitulate herein a recent analysis of proteinaceous waste deposition in the human brain, its observed route of clearance, and the implications of abnormal accumulation along this clearance pathway as a potential mechanism of neurological diseases. This study uncovered an analogous staining pattern of cerebral phosphorylated tau in temporal lobe epilepsy (TLE) and chronic traumatic encephalopathy (CTE). Regardless of the underlying physiopathology, p-tau elimination occurred via circulation through the perivenous space, as predicted by a glymphatic route of clearance. Remarkably, we demonstrated that p-tau is associated with a neurological disease that can develop independent of head trauma, since in both CTE and TLE: 1) Extracellular p-tau followed unidirectional, fluid-driven pathways that led toward the space bordering large (>100 µm diameter) blood vessels; 2) Tau-positive staining occurred within astroglial cells adjacent to blood vessels, which signified transcellular transport of p-tau as a potential secondary efflux route; 3) P-tau frequently appeared clustered within the perivenous space. This waste aggregation bears significant implications in the disruption of interstitial fluid circulation, which may contribute to exacerbation of disease states. A better understanding of waste elimination in the human brain may prove significant as a therapeutic target to improve parenchymal fluid circulation, and consequently, mitigate the hydrostatic, osmotic and oncotic imbalances that often cause or exacerbate brain diseases.

Extracellular uridine diphosphate-mediated microglial inflammation in a mouse model of Sandhoff disease

Eri Kawashita¹, Daisuke Tsuji², Kohji Itoh^2*

 Sandhoff disease (SD) is an inherited lysosomal storage disease caused by a β-hexosaminidase deficiency involving excessive accumulation of undegraded substrates, including GM2 ganglioside, which leads to neurological symptoms, such as mental retardation, spasms and quadriplegia. Macrophage inflammatory protein-1α (MIP-1α) is a crucial factor for microglia-mediated neuroinflammation in the onset or progression of SD. However, there was no therapeutic approach to control the abnormal production of MIP-1α in the brain of SD, and the mechanisms underlying the MIP-1α production by microglia, especially the transmitter-mediated production, remains unclear.

Extracellular nucleotides, including uridine diphosphate (UDP), are leaked by injured or damaged neurons. It has been shown that the nucleotide leakage activates microglia to trigger chemotaxis, phagocytosis, macropinocytosis and cytokine production, suggesting that extracellular nucleotides may be important neurotransmitters for microglia to regulate their functions physiologically and pathologically.

In the present study, we review the essential roles of extracellular nucleotides in the microglial functions and the UDP-enhanced MIP-1α production by microglia in SD model mice, providing a potential therapeutic approach for SD.

Commentary: A novel infection- and inflammation-associated molecular signature in peripheral blood of myasthenia gravis patients

Claudia Barzago¹, Pia Bernasconi¹, Raffaele A. Calogero², Carlo Antozzi¹, Francesca Zolezzi³, Renato Mantegazza^1# and Lucia Mori^4*

Early-onset acetylcholine receptor-positive myasthenia gravis is the most studied and better-characterized clinical subgroup of myasthenia gravis. Here we discuss the results of the first comprehensive and unbiased transcriptome sequencing analysis performed on circulating cells of a clinically homogeneous cohort of patients affected by this disease form.

Commentary: alpha-synuclein interacts with SOD1 and promotes its oligomerization

Anika M. Helferich¹, Pamela J. McLean², Jochen H. Weishaupt¹ and Karin M. Danzer^1*

¹Department of Neurology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany
²Mayo Clinic, Jacksonville, Florida, USA

Alpha-synuclein and Cu, Zn superoxide dismutase (SOD1) are both aggregation-prone proteins that are associated with Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), respectively. Recently, we showed that alpha-synuclein interacts with SOD1 in various cell types and tissues. Using a cell culture model, we also found that alpha-synuclein nucleates the polymerization of SOD1. Here, we discuss the current literature regarding their interaction and their co-localization in aggregates of human post-mortem tissue. Furthermore we comment on the reported alpha-synuclein-induced SOD1 polymerization in terms of cross-seeding effects in neurodegeneration.

TrkB and the calpain dependent-Tc TrkB receptor isoforms: possible neurological therapeutic targets

Víctor Danelon¹, Andrea B. Cragnolini¹, Daniel Masco^1*

Several neurological conditions share a characteristic feature: an increase in intracellular calcium levels ([Ca2+]i). It has been demonstrated that calcium influx induces changes ranging from an increase in the expression levels of several genes to the activation of proteases such as calpains. Calpains are a family of Ca2+-dependent non-lysosomal cysteine proteases, whose substrates include several proteins that play critical roles in several cellular functions including synaptic plasticity and neuronal apoptosis.

TrkB is a type of tyrosine related kinase receptor that can promote neuronal survival and differentiation upon ligand binding. It has been recently shown that in several neurological diseases, the level of full-length TrkB protein decreases before the onset of neuronal death due to one of two different processes: a) a reverse regulation of TrkB isoforms mRNA, or b) calpain-mediated processing of TrkB full-length, which yields a truncated form of TrkB (Tc-TrkB). Because the most notorious feature of calpain proteolytic activity is that the products of calpain-mediated cleavage may have biological activity, here we review the hypotheses by which calpain-generated isoform Tc-TrkB may perform biological functions.

Neuropathies of Stuve-Wiedemann Syndrome due to mutations in leukemia inhibitory factor receptor (LIFR) gene

Alexandra E. Oxford, Cheryl L. Jorcyk, Julia Thom Oxford*

 Stüve-Wiedemann syndrome (STWS; OMIM #610559) is a rare disease that results in dysfunction of the autonomic nervous system, which controls involuntary processes such as breathing rate and body temperature. In infants, this can result in respiratory distress, feeding and swallowing difficulties, and hyperthermic episodes. Individuals may sweat excessively when body temperature is not elevated. Additionally, individuals have reduced ability to feel pain and may lose reflexes such as the corneal reflex that normally causes one to blink, and the patellar reflex resulting in the knee-jerk. STWS usually results in infant mortality, yet some STWS patients survive into early adulthood. STWS is caused by a mutation in the leukemia inhibitory factor receptor (LIFR) gene, which is inherited in an autosomal-recessive pattern. Most LIFR mutations resulting in STWS cause instability of the mRNA due to frameshift mutations leading to premature stop codons, which prevent the formation of LIFR protein. STWS is managed on a symptomatic basis as no treatment is currently available.

A Case of Misdiagnosed Juvenile Dermatomyositis

Wang Liang¹, Xu Min², Sun Yiming³, Zhang Cheng^1*

Objective: To report a misdiagnosed case in order to avoid similar misdiagnosis of atypical juvenile dermatomyositis as muscular dystrophy in neurological clinics.

Methods: The process of misdiagnosis was first described. Thereafter, the patient’s diagnosis and treatment effect at the six-month follow-up were evaluated, and reported here.

Results: The patient presented an atypical course of juvenile dermatomyositis. The rashes, which mainly presented as erythema and wheals, were subsequently followed by the appearance of muscle weakness. However, the rashes were inconspicuous at first consult. The misdiagnosis of Duchenne muscular dystrophy was made due to the age of onset, distribution of muscle weakness, a high creatine kinase level, and other serum enzymatic changes. Upon further analysis, however, a diagnosis of juvenile dermatomyositis was definitively confirmed and the disease was controlled following systematic treatment for five months.

Conclusion: Although atypical juvenile dermatomyositis has a manifestation similar to that of muscular dystrophy, the considerations outlined in this case report will be helpful to avoid similar misdiagnosis.