Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity

Neurodegenerative diseases constitute a class of illnesses marked by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the degeneration of highly specific subpopulations of neurons, protein aggregation occurs in all cells, which indicates that toxicity arises only in particular cell biological contexts. Aggregation-associated disorders are unified by a common cell biological feature: the deposition of the culprit proteins in inclusion bodies. The precise function of these inclusions remains unclear. The starting point for uncovering the origins of disease pathology must therefore be a thorough understanding of the general cell biological function of inclusions and their potential role in modulating the consequences of aggregation. Here, we show that in human cells certain aggregate inclusions are active compartments. We find that toxic aggregates localize to one of these compartments, the juxtanuclear quality control compartment (JUNQ), and interfere with its quality control function. The accumulation of SOD1G93A aggregates sequesters Hsp70, preventing the delivery of misfolded proteins to the proteasome. Preventing the accumulation of SOD1G93A in the JUNQ by enhancing its sequestration in an insoluble inclusion reduces the harmful effects of aggregation on cell viability.     

DNA-fragmentation and apoptosis-related proteins of muscle cells in motor neuron disorders

Apoptosis has been decribed as one of the mechanisms of muscle fiber loss in infantile spinal muscular atrophy. In order to investigate if muscle fiber-apoptosis plays a role in other denervating disorders as well, we studied DNA-fragmentation, a hallmark of apoptosis, by the TUNEL-method and, moreover, the expression patterns of apoptosis-related proteins in 2 patients suffering from ALS and in 6 patients with polyneuropathy. We identified DNA-cleavage in muscle fibers of all these patients. Furthermore, we found strong expression of bax and ICE promoting apoptosis in muscle fibers. However, also strong expression of the anti-apoptotic factor bcl-2 was found. Our findings indicate that defective innervation may prompt muscle fibers to activate an intrinsic "suicide" programme which is promoted by the pro-apoptotic factors bax and ICE, which seems to induce formation of apoptotic bodies by cleavage of actin. Nevertheless, there are also anti-apoptotic strategies in muscle fibers manifested by expression of the bax-antagonist bcl-2 which is able to neutralize high bax levels.     

肌萎缩侧索硬化患者血浆和脑脊液谷氨酸改变及利鲁唑对血浆谷氨酸的影响

目的 :了解肌萎缩侧索硬化 (ALS)患者血浆和脑脊液谷氨酸浓度改变 ,以及药物干预对谷氨酸水平的影响。方法 :应用HPLC方法对ALS患者进行血浆和脑脊液谷氨酸测定。结果 :①患者血浆中存在兴奋性谷氨酸显著增高 ,谷氨酸浓度与性别、年龄、病程均无关。②力鲁唑 (力如太 )治疗 1个月后 ,血浆谷氨酸浓度下降 ,而环磷酰胺治疗变化不明显。③脑脊液中谷氨酸浓度未见明显变化。结论 :ALS患者存在谷氨酸代谢异常 ,但谷氨酸可能不是ALS致病的惟一途径。     

Use of single fiber EMG and macro EMG in study of reinnervation

The use of single fiber EMG and macro EMG in studies of reinnervation is discussed. SFEMG gives information about changes in the topography of the motor unit and in function of transmission in terminal nerve, motor endplate and muscle fiber. Dynamics of reinnervation may be studied with this technique. The amount of reinnervation is obtained from macro EMG studies. The capacity for reinnervation is discussed for a few conditions as well as factors that limit the reinnervation process.     

Glyoxal inactivates glutamate transporter‐1 in cultured rat astrocytes

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor paralysis and selective motor neuron death. There is increasing evidence that motor neuron death in ALS is mediated by glutamate toxicity resulting from reduced activity of astrocytic glutamate transporter‐1 (GLT‐1). Recent morphological studies have shown that N^?‐(carboxymethyl)lysine (CML) accumulates in reactive astrocytes of ALS spinal cords. CML is a product of post‐translational protein modification by glyoxal, a reactive aldehydic intermediate. In considering these documents, it is important to determine whether GLT‐1 protein modification by glyoxal might cause reduced GLT‐1 activity. To address this issue, we investigated the effects of glyoxal on GLT‐1 properties in cultured rat astrocytes. High performance liquid chromatography showed reduced glutamate uptake activity in the glyoxal‐exposed cells. Immunocytochemical analysis displayed CML accumulation in the cytoplasm of astrocytes by glyoxal exposure. Immunoblots of immunoprecipitated GLT‐1 disclosed GLT‐1 CML adduct formation in the glyoxal‐exposed cells. Our results indicate that glyoxal modifies GLT‐1 to form CML and simultaneously deprives its glutamate uptake activity. Thus, these toxic effects of glyoxal on astrocytes might be implicated in motor neuron death in ALS.     

Titration of Mechanical Insufflation–Exsufflation Optimal Pressure Combinations in Neuromuscular Diseases by Flow/Pressure Waveform Analysis

Introduction

The aim of this study was to assess several air-pressure settings for MI–E to determine their effect on peak cough flow (PCF), and to compare the best pressures with those are more common used in the literature (±40 cmH₂O) in patients with neuromuscular disorders (NMD).

Peripheral nerve ultrasound in amyotrophic lateral sclerosis phenotypes

Introduction: In this study we sought to determine the cross‐sectional area (CSA) of peripheral nerves in patients with distinct subtypes of amyotrophic lateral sclerosis (ALS). Methods: Ulnar and median nerve ultrasound was performed in 78 ALS patients [classic, n = 21; upper motor neuron dominant (UMND), n = 14; lower motor neuron dominant (LMND), n = 20; bulbar, n = 15; primary lateral sclerosis (PLS), n = 8] and 18 matched healthy controls. Results: Compared with controls, ALS patients had significant, distally pronounced reductions of ulnar CSA (forearm/wrist level) across all disease groups, except for PLS. Median nerve CSA (forearm/wrist level) did not differ between controls and ALS. Conclusion: Ulnar nerve ultrasound in ALS subgroups revealed significant differences in distal CSA values, which suggests it has value as a marker of LMN involvement. Its potential was particularly evident in the UMND and PLS groups, which can be hard to separate clinically, yet their accurate separation has major prognostic implications. Muscle Nerve 51 :669–675, 2015