Molecular pathology and genetic advances in amyotrophic lateral sclerosis: An emerging molecular pathway and the significance of glial pathology

Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK.
Acta Neuropathologica (Impact Factor: 10.76). 11/2011; 122(6):657-71. DOI: 10.1007/s00401-011-0913-0
Source: PubMed


Research into amyotrophic lateral sclerosis (ALS) has been stimulated by a series of genetic and molecular pathology discoveries. The hallmark neuronal cytoplasmic inclusions of sporadic ALS (sALS) predominantly comprise a nuclear RNA processing protein, TDP-43 encoded by the gene TARDBP, a discovery that emerged from high throughput analysis of human brain tissue from patients with frontotemporal dementia (FTD) who share a common molecular pathology with ALS. The link between RNA processing and ALS was further strengthened by the discovery that another genetic locus linking familial ALS (fALS) and FTD was due to mutation of the fused in sarcoma (FUS) gene. Of potentially even greater importance it emerges that TDP-43 accumulation and inclusion formation characterises not only most sALS cases but also those that arise from mutations in several genes including TARDBP (predominantly ALS cases) itself, C9ORF72 (ALS and FTD cases), progranulin (predominantly FTD phenotypes), VAPB (predominantly ALS cases) and in some ALS cases with rare genetic variants of uncertain pathogenicity (CHMP2B). "TDP-proteinopathy" therefore now represents a final common pathology associated with changes in multiple genes and opens the possibility of research by triangulation towards key common upstream molecular events. It also delivers final proof of the hypothesis that ALS and most FTD cases are disorders within a common pathology expressed as a clinico-anatomical spectrum. The emergence of TDP-proteinopathy also confirms the view that glial pathology is a crucial facet in this class of neurodegeneration, adding to the established view of non-nerve cell autonomous degeneration of the motor system from previous research on SOD1 fALS. Future research into the mechanisms of TDP-43 and FUS-related neurodegeneration, taking into account the major component of glial pathology now revealed in those disorders will significantly accelerate new discoveries in this field, including target identification for new therapy.

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Available from: Janine Kirby, Jan 08, 2014
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    • "Motor neurons from SOD1 G93A mice, which overexpress this human mutant SOD1 protein, also show hyperexcitability (Kuo et al., 2004; Pieri et al., 2003; van Zundert et al., 2008), at least in part due to increased persistent sodium currents. Because of the distinct clinical and pathological features of SOD1 ALS compared to other variants (Ince et al., 2011), it is unclear if primary motor neuron hyperexcitability represents a general feature of ALS or a specific characteristic of SOD1-mediated disease. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor nervous system. We show using multielectrode array and patch-clamp recordings that hyperexcitability detected by clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (SOD1), C9orf72, and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected but otherwise isogenic SOD1(+/+) stem cell line do not display the hyperexcitability phenotype. SOD1(A4V/+) ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival in vitro when tested in SOD1 mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates.
    Cell Reports 04/2014; 7(1). DOI:10.1016/j.celrep.2014.03.019 · 8.36 Impact Factor
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    • "Amyotrophic lateral sclerosis (ALS) is described as a degenerative disease involving loss of the upper and lower motor neurons from motor cortex, brain stem and spinal cord leading to muscle denervation, wasting and death. There is now increasing evidence that other cell types are involved and the precise pattern of degeneration is unclear (Ince et al., 2011). Multiple mutually compatible mechanisms have been implicated in the pathogenesis of the disease including oxidative stress, excitotoxicity, ubiquitin and proteasome dysfunction, inflammatory activation, RNA processing dysregulation, mitochondrial dysfunction, cytoskeletal abnormalities and activation of apoptosis (Ferraiuolo et al., 2011). "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by degeneration and loss of upper and lower motor neurons from the motor cortex, brainstem and spinal cord although evidence is suggesting that there is further involvement of other cell types in the surrounding tissue. Transcriptomic analysis by gene expression profiling using microarray technology has enabled the determination of patterns of cell death in the degenerating tissues. This work has examined gene expression at the level of the tissue and individual cell types in both sporadic and familial forms of the disease. In addition, further studies have examined the differential vulnerability of neuronal cells in different regions of the central nervous system. Model systems have also provided further information to help unravel the mechanisms that lead to death of the motor neurons in disease and also provided novel insights. In this review we shall describe the methods that have been used in these investigations and describe how they have contributed to our knowledge of the cell death mechanisms in ALS.
    Frontiers in Cellular Neuroscience 12/2013; 7:259. DOI:10.3389/fncel.2013.00259 · 4.29 Impact Factor
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    • "O  to hydrogen peroxide [3] [4]. Recently, other mutations involved in FALS cases have been discovered (TARDBP, FUS, C9ORG72,) [5]. Moreover, the finding of C9orf72 hexanucleotide repeat expansion in both sporadic and familial ALS suggests that many apparently sporadic cases are in fact underestimated familial cases [6] [7]. "
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    ABSTRACT: The amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disor-der primarily involving motoneurons in the ce-rebral cortex, brainstem, and spinal cord. SOD1-G93A mice, which express multiple cop-ies of the mutant form of the human Cu/Zn SOD, are one of the most widely used animal models for ALS pathology. However, the onset of the disease can vary between animals of 1 -2 weeks while the progression is quite fast. In order to evaluate the efficacy of any treatment, it is very important to treat all animals at the early onset of the disease, instead of at a fixed age-point. To this aim, we performed behavioral analysis and measured hSOD1 mRNA expression to identify the appearance of the first motor deficits. Ro-tarod and PaGE tests revealed to be the most sensitive approaches to detect the beginning of the symptomatic phase of the disease, while neurological score and weight monitoring showed significant differences only at later stages in ALS pathology. Furthermore, we found a better correlation between hSOD1 mRNA expression with disease onset than with a transgene copy number. Therefore, the association of behavioral tests and molecular analysis represents a sen-sible and accurate tool to early detect the mur-ine symptoms.
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