Mitochondrial involvement in amyotrophic lateral sclerosis

Despite numerous reports demonstrating mitochondrial abnormalities associated with amyotrophic lateral sclerosis (ALS), the role of mitochondrial dysfunction in the disease onset and progression remains unknown. The intrinsic mitochondrial apoptotic program is activated in the central nervous system of mouse models of ALS harboring mutant superoxide dismutase 1 protein. This is associated with the release of cytochrome-c from the mitochondrial intermembrane space and mitochondrial swelling. However, it is unclear if the observed mitochondrial changes are caused by the decreasing cellular viability or if these changes precede and actually trigger apoptosis. This article discusses the current evidence for mitochondrial involvement in familial and sporadic ALS and concludes that mitochondria is likely to be both a trigger and a target in ALS and that their demise is a critical step in the motor neuron death.     

Mitochondrial dysfunction in amyotrophic lateral sclerosis

The etiology of motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remains to be better understood. Based on the studies from ALS patients and transgenic animal models, it is believed that ALS is likely to be a multifactorial and multisystem disease. Many mechanisms have been postulated to be involved in the pathology of ALS, such as oxidative stress, glutamate excitotoxicity, mitochondrial damage, defective axonal transport, glia cell pathology and aberrant RNA metabolism. Mitochondria, which play crucial roles in excitotoxicity, apoptosis and cell survival, have shown to be an early target in ALS pathogenesis and contribute to the disease progression. Morphological and functional defects in mitochondria were found in both human patients and ALS mice overexpressing mutant SOD1. Mutant SOD1 was found to be preferentially associated with mitochondria and subsequently impair mitochondrial function. Recent studies suggest that axonal transport of mitochondria along microtubules and mitochondrial dynamics may also be disrupted in ALS. These results also illustrate the critical importance of maintaining proper mitochondrial function in axons and neuromuscular junctions, supporting the emerging “dying-back” axonopathy model of ALS. In this review, we will discuss how mitochondrial dysfunction has been linked to the ALS variants of SOD1 and the mechanisms by which mitochondrial damage contributes to the disease etiology.     

Mitochondrial dysfunction in familial amyotrophic lateral sclerosis

A growing body of evidence suggests that mitochondrial dysfunctions play a crucial role in the pathogenesis of various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting both upper and lower motor neurons. Although ALS is predominantly a sporadic disease, approximately 10% of cases are familial. The most frequent familial form is caused by mutations in the gene encoding Cu/Zn superoxide dismutase 1 (SOD1). A dominant toxic gain of function of mutant SOD1 has been considered as the cause of the disease and mitochondria are thought to be key players in the pathogenesis. However, the exact nature of the link between mutant SOD1 and mitochondrial dysfunctions remains to be established. Here, we briefly review the evidence for mitochondrial dysfunctions in familial ALS and discuss a possible link between mutant SOD1 and mitochondrial dysfunction.     

Possible involvement of folate cycle in the pathogenesis of amyotrophic lateral sclerosis

The folate cycle, which has a close correlation with nucleic acid synthesis as well as with sulfur amino acid metabolism, may have some bearing on the pathogenesis of amyotrophic lateral sclerosis. The folate cycle hypothesis offers a unified explanation of the reduction of RNA and the elevation of taurine in nervous tissue of this disease.Dedicated to K. A. C. Elliott on his 80th birthday.     

Neurovascular signals in amyotrophic lateral sclerosis

The image recapitulates the interplay between neuronal and vascular systems by highlighting the cellular players involved in the molecular signalling in the context of Amyotrophic Lateral Sclerosis.

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The neurovascular system (NVS) is a complex anatomic-functional unit that synergically works to maintain organs/tissues homeostasis of the entire body. NVS alterations have recently emerged as a common distinct feature in the pathogenesis of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Despite their undeniable involvement, neurovascular signalling pathways remain still far unknown in ALS. This review underlines the importance of endothelial, mural, and fibroblast cells as novel targets for ALS investigation and identifies in the interplay between neuronal and vascular systems the way to disclose novel molecular mechanisms behind the pathogenesis of ALS.     

Innate immunity in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in which motor neurons are selectively targeted. Although the underlying cause remains unclear, evidence suggests a role for innate immunity in disease pathogenesis. Neuroinflammation in areas of motor neuron loss is evident in presymptomatic mouse models of ALS and in human patients. Efforts aimed at attenuating the inflammatory response in ALS animal models have delayed symptom onset and extended survival. Seemingly conversely, attempts to sensitize cells of the innate immune system and modulate their phenotype have also shown efficacy. Effectors of innate immunity in the CNS appear to have ambivalent potential to promote either repair or injury. Because ALS is a syndromic disease in which glutamate excitotoxicity, altered cytoskeletal protein metabolism, oxidative injury, mitochondrial dysfunction and neuroinflammation all contribute to motor neuron degeneration, targeting inflammation via modulation of microglial function therefore holds significant potential as one aspect of therapeutic intervention and could provide insight into the exclusive vulnerability of motor neurons.     

Chromogranin peptides in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which primarily affects motor neurons. Eight cases of ALS and seven control cases were studied with semiquantitative immunocytochemistry for chromogranin A, chromogranin B and secretogranin II that are soluble constituents of large dense core vesicles, synaptophysin as a membrane protein of small synaptic vesicles and superoxide dismutase 1. Among the chromogranin peptides, the number and staining intensity of motor neurons was highest for chromogranin A. In ALS, the staining intensity for chromogranin peptides and synaptophysin was significantly lower in the ventral horn of ALS patients due to a loss in immunoreactive motor neurons, varicose fibers and varicosities. For all chromogranins, the remaining motor neurons displayed a characteristic staining pattern consisting of an intracellular accumulation of immunoreactivity with a high staining intensity. Confocal microscopy of motor neurons revealed that superoxide dismutase 1-immunopositive intracellular aggregates also contained chromogranin A, chromogranin B and secretogranin II. These findings indicate that there is a loss of small and large dense core vesicles in presynaptic terminals. The intracellular co-occurrence of superoxide dismutase 1 and chromogranins may suggest a functional interaction between these proteins. This study should prompt further experiments to elucidate the role of chromogranins in ALS patients.     

Mitochondrial proteomic analysis of a cell line model of familial amyotrophic lateral sclerosis

Mutations in copper-zinc superoxide dismutase (SOD1) have been linked to a subset of familial amytrophic lateral sclerosis (fALS), a fatal neurodegenerative disease characterized by progressive motor neuron death. An increasing amount of evidence supports that mitochondrial dysfunction and apoptosis activation play a critical role in the fALS etiology, but little is known about the mechanisms by which SOD1 mutants cause the mitochondrial dysfunction and apoptosis. In this study, we use proteomic approaches to identify the mitochondrial proteins that are altered in the presence of a fALS-causing mutant G93A-SOD1. A comprehensive characterization of mitochondrial proteins from NSC34 cells, a motor neuron-like cell line, was achieved by two independent proteomic approaches. Four hundred seventy unique proteins were identified in the mitochondrial fraction collectively, 75 of which are newly discovered proteins that previously had only been reported at the cDNA level. Two-dimensional gel electrophoresis was subsequently used to analyze the differences between the mitochondrial proteomes of NSC34 cells expressing wild-type and G93A-SOD1. Nine and 36 protein spots displayed elevated and suppressed abundance respectively in G93A-SOD1-expressing cells. The 45 spots were identified by MS, and they include proteins involved in mitochondrial membrane transport, apoptosis, the respiratory chain, and molecular chaperones. In particular, alterations in the post-translational modifications of voltage-dependent anion channel 2 (VDAC2) were found, and its relevance to regulating mitochondrial membrane permeability and activation of apoptotic pathways is discussed. The potential role of other proteins in the mutant SOD1-mediated fALS is also discussed. This study has produced a short list of mitochondrial proteins that may hold the key to the mechanisms by which SOD1 mutants cause mitochondrial dysfunction and neuronal death. It has laid the foundation for further detailed functional studies to elucidate the role of particular mitochondrial proteins, such as VDAC2, in the pathogenesis of familial ALS.     

Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease that causes degeneration of motoneurons. Mutation of Cu,Zn superoxide dismutase (SOD1) is one cause for this disease. In mice, expression of mutant protein causes motoneuron degeneration and paralysis resembling the human disease. Morphological change, indicative of mitochondrial damage, occurs at early stages of the disease. To determine whether mitochondrial function changes during the course of disease progression, enzyme activities of mitochondrial electron transport chain in spinal cords from mice at different disease stages were measured using three different methods: spectrophotometric assay, in situ histochemical enzyme assay, and blue native gel electrophoresis combined with in-gel histochemical reaction. The enzyme activities were decreased in the spinal cord, particularly in the ventral horn, beginning at early disease stages. This decrease persisted throughout the course of disease progression. This decrease was not detected in the spinal cords of non-transgenic animals, of mice expressing the wild-type protein, and in cerebellum and dorsal horn of the spinal cords from mice expressing mutant protein. These results demonstrate a functional defect in mitochondria in the ventral horn region and support the view that mitochondrial damage plays a role in mutant SOD1-induced motoneuron degeneration pathway.     

SOD1 oligomers in amyotrophic lateral sclerosis

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Growth factor receptors in amyotrophic lateral sclerosis

The regional distribution of nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1) receptors in human spinal cords from controls and amyotrophic lateral sclerosis (ALS) patients was studied by quantitative autoradiography. High-affinity nerve growth factor receptors were found to be distributed to a similar extent within the various segments of the human spinal cord and predominantly within the substantia gelatinosa of the dorsal horn, whereas no significant binding could be detected in the motor-neuron areas. A similar pattern of binding was obtained in the ALS spinal cords. Moreover, no reexpression of NGF receptors could be demonstrated in the motor-neuron areas of ALS spinal cords. When comparing¹²⁵I-IGF-1 binding in the different spinal levels of normal spinal cord, the same distribution pattern was found in which the binding was highest in the central canal > dorsal horn > ventral horn > white matter. In the ALS cases, although a general upregulation of IGF-1 receptors was observed throughout the spinal cord, significant increases were observed in the cervical and sacral segments compared to controls. The cartography of IGF-1 receptors in the normal spinal cord as well as the change of these receptors in diseased spinal cord may be of importance in future treatment strategies of ALS.     

Cyclin-dependent kinase 5 in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a neurological disorder that selectively affects motor neurons of brain and spinal cord. Emerging evidence indicates an involvement of the serine/threonine-cyclin-dependent kinase 5 (Cdk5) in the pathogenesis. Deregulation of Cdk5 by its truncated co-activators, p25 and p29, contributes to neurodegeneration by altering the phosphorylation state of cytosolic and cytoskeletal proteins and, possibly, through the induction of cell cycle regulators. The present paper reviews these findings and proposes new perspectives to decipher the mechanisms of neurodegeneration in amyotrophic lateral sclerosis induced by Cdk5.     

Protein biomarkers for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with largely unknown pathogenesis that typically results in death within a few years from diagnosis. There are currently no effective therapies for ALS. Clinical diagnosis usually takes several months to complete and the long delay between symptom onset and diagnosis limits the possibilities for effective intervention and clinical trials. The establishment of protein biomarkers for ALS may aid an earlier diagnosis, facilitating the search for effective therapeutic interventions and monitoring drug efficacy during clinical trials. Biomarkers could also be used to discriminate between subtypes of ALS, to measure disease progression and to detect susceptibility for developing ALS or monitor adverse effects of drug treatment. The present review will discuss the opportunities and proteomic platforms used for biomarker discovery efforts in ALS, summarizing putative ALS protein biomarkers identified in different biofluids.     

THyroliberin test in patients with amyotrophic lateral sclerosis

Many hormonal dysfunctions were noticed in amyotrophic lateral sclerosis (ALS). The study aimed at measuring blood serum level of TSH and PRL after THR loading in 10 ALS patients and in the 10 healthy individuals. Mean baseline levels of TSH and PRL in ALS patients were with in normal range. After TRH loading, the TSH responses in the ALS patients were with in normal range, where as PRL responses were diminished. The obtained results could indicate some disorders on the dopaminergic neurons level.     

Impaired structural motor connectome in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease selectively affecting upper and lower motor neurons. Patients with ALS suffer from progressive paralysis and eventually die on average after three years. The underlying neurobiology of upper motor neuron degeneration and its effects on the complex network of the brain are, however, largely unknown. Here, we examined the effects of ALS on the structural brain network topology in 35 patients with ALS and 19 healthy controls. Using diffusion tensor imaging (DTI), the brain network was reconstructed for each individual participant. The connectivity of this reconstructed brain network was compared between patients and controls using complexity theory without - a priori selected - regions of interest. Patients with ALS showed an impaired sub-network of regions with reduced white matter connectivity (p = 0.0108, permutation testing). This impaired sub-network was strongly centered around primary motor regions (bilateral precentral gyrus and right paracentral lobule), including secondary motor regions (bilateral caudal middle frontal gyrus and pallidum) as well as high-order hub regions (right posterior cingulate and precuneus). In addition, we found a significant reduction in overall efficiency (p = 0.0095) and clustering (p = 0.0415). From our findings, we conclude that upper motor neuron degeneration in ALS affects both primary motor connections as well as secondary motor connections, together composing an impaired sub-network. The degenerative process in ALS was found to be widespread, but interlinked and targeted to the motor connectome.