ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules

Infantile-onset Ascending Hereditary Spastic Paralysis, Juvenile Primary Lateral Sclerosis and Juvenile Amyotrophic Lateral Sclerosis are all motor neuron diseases related to mutations on the ALS2 gene, encoding for a 1657 amino acids protein named Alsin. This ~185 kDa multi-domain protein is ubiquitously expressed in various human tissues, mostly in the brain and the spinal cord. Several investigations have indicated how mutations within Alsin’s structured domains may be responsible for the alteration of Alsin’s native oligomerization state or Alsin’s propensity to interact with protein partners. In this review paper, we propose a description of differences and similarities characterizing the above-mentioned ALS2-related rare neurodegenerative disorders, pointing attention to the effects of ALS2 mutation from molecule to organ and at the system level. Known cases were collected through a literature review and rationalized to deeply elucidate the neurodegenerative clinical outcomes as consequences of ALS2 mutations.

Saccharomyces boulardii improves the behaviour and emotions of spastic cerebral palsy rats through the gut-brain axis pathway

Background Cerebral palsy (CP) is a kind of disability that influences motion, and children with CP also exhibit depression-like behaviour. Inflammation has been recognized as a contributor to CP and depression, and some studies suggest that the gut-brain axis may be a contributing factor. Our team observed that Saccharomyces boulardii (S. boulardii) could reduce the inflammatory level of rats with hyperbilirubinemia and improve abnormal behaviour. Both CP and depression are related to inflammation, and probiotics can improve depression by reducing inflammation. Therefore, we hypothesize that S. boulardii may improve the behaviour and emotions of spastic CP rats through the gut-brain axis pathway. Methods Our new rat model was produced by resecting the cortex and subcortical white matter. Seventeen-day-old CP rats were exposed to S. boulardii or vehicle control by gastric gavage for 9 days, and different behavioural domains and general conditions were tested. Inflammation was assessed by measuring the inflammatory markers IL-6 and TNF-α. Hypothalamic–pituitary–adrenal (HPA) axis activity was assessed by measuring adrenocorticotropic hormone and corticosterone in the serum. Changes in the gut microbiome were detected by 16S rRNA. Results The hemiplegic spastic CP rats we made with typical spastic paralysis exhibited depression-like behaviour. S. boulardii treatment of hemiplegic spastic CP rats improves behaviour and general conditions and significantly reduces the level of inflammation, decreases HPA axis activity, and increases gut microbiota diversity. Conclusions The model developed in this study mimics a hemiplegic spastic cerebral palsy. Damage to the cortex and subcortical white matter of 17-day-old Sprague–Dawley (SD) rats led to spastic CP-like behaviour, and the rats exhibited symptoms of depression-like behaviour. Our results indicate that S. boulardii might have potential in treating hemiplegic spastic CP rat models or as an add-on therapy via the gut-brain axis pathway.

A p.Arg499His mutation in SPAST is associated with infantile-onset complicated spastic paraplegia: a case report and review of the literature

Background Spastic paraplegia type 4 (SPG4) is caused by mutations in the SPAST gene, is the most common form of autosomal-dominant pure hereditary spastic paraplegias (HSP), and is rarely associated with a complicated form that includes ataxia, epilepsy, and cognitive decline. To date, the genotype-phenotype correlation has not been substantially established for SPAST mutations. Case presentation We present a Japanese patient with infantile-onset HSP and a complex form with coexisting ataxia and epilepsy. The sequencing of SPAST revealed a de novo c.1496G > A (p.R499H) mutation. A review of the literature revealed 16 additional patients with p.R499H mutations in SPAST associated with an early-onset complicated form of HSP. We found that the complicated phenotype of patients with p.Arg499His mutations could be mainly divided into three subgroups: (1) infantile-onset ascending hereditary spastic paralysis, (2) HSP with severe dystonia, and (3) HSP with cognitive impairment. Moreover, the c.1496G > A mutation in SPAST may occur as a de novo variant at noticeably high rates. Conclusion We reviewed the clinical features of the patients reported in the literature with the p.Arg499His mutation in SPAST and described the case of a Japanese patient with this mutation presenting a new complicated form. Accumulating evidence suggests a possible association between infantile-onset complicated HSP and the p.Arg499His mutation in SPAST. The findings of this study may expand the clinical spectrum of the p.Arg499His mutation in SPAST and provide an opportunity to further study the genotype-phenotype correlation of SPG4.

Elucidating molecular connetion between IAHSP onset and Alsin protein by means of Homology Modelling and Molecular Dynamics

The Infantile-onset Ascending Hereditary Spastic Paralysis (IAHSP) is an incurable rare neurodegerative disease related to a mutation-driven aberrant behaviour of the Alsin protein. The lack of information on Alsin atomic structure limits a complete understanding on pathology mechanisms. In this work, molecular modelling techniques have been applied to shed lights on Alsin folding dynamics and misfunction induced by aberrant mutations.

Anthelmintic resistance and homeostatic plasticity (Brugia malayi)

Homeostatic plasticity refers to the capacity of excitable cells to regulate their activity to make compensatory adjustments to long-lasting stimulation. It is found across the spectrum of vertebrate and invertebrate species and is driven by changes in cytosolic calcium; it has not been explored in parasitic nematodes when treated with therapeutic drugs. Here we have studied the adaptation of Brugia malayi to exposure to the anthelmintic, levamisole that activates muscle AChR ion-channels. We found three phases of the Brugia malayi motility responses as they adapted to levamisole: an initial spastic paralysis; a flaccid paralysis that follows; and finally, a recovery of motility with loss of sensitivity to levamisole at 4 h. Motility, calcium-imaging, patch-clamp and molecular experiments showed the muscle AChRs are dynamic with mechanisms that adjust their subtype composition and sensitivity to levamisole. This homeostatic plasticity allows the parasite to adapt resisting the anthelmintic.

Clinical Study of Acupotomy Trinity Lysis Combined with Rehabilitation Training for Spastic Paralysis after Stroke

Objective: To study the clinical efficacy of acupotomy trinity lysis combined with rehabilitation training in the treatment of spastic paralysis after stroke, and to provide guidance for clinical diagnosis and treatment. Methods: From July 2019 to November 2020, 119 patients with post-stroke spastic paralysis who were admitted to our hospital's encephalopathy department were selected as the research objects, and 61 patients were divided into acupuncture combined with rehabilitation training group as the observation group by random number table method. 58 patients were divided into the rehabilitation training group as the control group. After 21 days of treatment, they passed the modified Ashworth Spasm Scale (MAS) grading scale score, Clinical Spasm Index (clinical spasm index, CSI) assessment, Fugl-Meyer exercise function scale (FMA) ) Score, Modified Barthel Index Score, and compare the clinical efficacy after treatment. Results: After treatment, the total effective rate of the observation group (95.08%) was higher than that of the control group (86.21%), and the difference was statistically significant (P?0.05); Before treatment, the contrast difference of MAS, FMA, CSI scores and modified Barthel index scores of the two groups of patients is not statistically significant; After treatment, the MAS scores and CSI scores of the elbow and knee joints of the observation group [(1.52±0.81)(1.46±0.83)(5.87±2.12)] were significantly lower than those of the control group [(2.17±0.68) (2.03±0.79)( 8.36±2.41)]; FMA upper limb and lower limb scores and modified Barthel index [(51.87±4.41)(30.21±5.05)(72.41±5.81)] of the observation group were significantly higher than those of the control group [(44.26±4.78)(28.45) ±4.23) (68.65±6.09)], the difference was statistically significant (P<0.05). Conclusion: Acupotomy trinity lysis combined with rehabilitation training is effective in treating patients with post-stroke spastic paralysis. It provides a safe, reliable and clinically effective new program, which is worthy of popularization and application.

Filiform-Fire Needle for Upper Extremity Spastic Paralysis After Stroke: A Randomized Controlled Trial

Background: Filiform-fire-needle（FFN）has been used in clinical treatment of upper extremity spastic paralysis after stroke(UESPAS). This study will evaluate the effect of filiform-fire-needle in the treatment of UESPAS under the background of standardized clinical research, and study the relationship between the efficacy and the course of treatment, so as to provide high-quality evidence-based basis for further clinical treatment and future research design.Methods: A prospective randomized controlled study was conducted to evaluate the clinical efficacy of FFN acupuncture therapy for patients with UESPAS. UESPAS patients were recruited in Changhai Hospital, Shanghai, China and they were randomly divided into FFN acupuncture group (F group), filiform needle acupuncture group (A group) or rehabilitation treatment group (R group). During the 20-day treatment, the same acupoints were taken in A group and F group. F group was treated once every 2 days for a total of 10 times, while A group and R group were treated 8 d in a row and then rest for for 2 days for a total of 16 times. In this study, the primary outcome indicators were modified Ashworth scale (MAS), secondary results including Fugl-Meyer assessment of Upper Extremity Motor Function (FMA-UE), National Institutes of Health Stroke Scale (NIHSS), Barthel index (BI). The above scales were evaluated before treatment, 10 days and 20 days after treatment. The safety was evaluated by self-made acupuncture adverse reaction observation table.Results: A significant difference was observed in MAS, FMA-UE, BI, NIHSS in the three groups from pre- to post treatment. From the evaluation of the changes of MAS, the curative effect of F group was better than the other two groups after 10 days of treatment, and F group was better than the R group on the 20th day, but there was no significant difference among the three groups after follow-up. The the difference of FMA-UE score showed F group was higher than the other two groups after 20 days of treatment and follow-up. The change of BI score in group F was higher than that in group R after 10 days of treatment, and the change of BI score in group F was higher than that in the other two groups after 20 days of treatment and follow-up. No significant change in the score of NIHSS was found in three groups.Conclusions: FFN acupuncture therapy has an advantage in relieving upper limb spasm and improving the activities of daily life of stroke patients in the short term, and in the long term, FFN has advantages in improving the motor ability of spastic limbs and improving the ability of daily life of patients.