Pathways Disrupted in Human ALS Motor Neurons Identified through Genetic Correction of Mutant SOD1

Kiskinis, Evangelos; Sandoe, Jackson; Williams, Luis A.; Boulting, Gabriella L.; Moccia, Rob; Wainger, Brian J.; Han, Steve S.W.; Peng, Theodore; Thams, Sebastian; Mikkilineni, Shravani; Mellin, Cassidy; Merkle, Florian T.; Davis‐Dusenbery, Brandi N.; Ziller, Michael J.; Oakley, Derek H.; Ichida, Justin K.; Costanzo, Stefania Di; Atwater, Nick; Maeder, Morgan L.; Goodwin, Mathew J.; Nemesh, James; Handsaker, Robert E.; Paull, Daniel; Noggle, Scott; McCarroll, Steven A.; Joung, J. Keith; Woolf, Clifford J.; Brown, Robert H.; Eggan, Kevin

doi:10.1016/j.stem.2014.04.005

Cited by 33 publications

(37 citation statements)

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“…In contrast to other types of neurons [e.g., cerebellar, cortical, pyramidal (59,60)], motor neurons have a particularly high threshold for induction of the heat shock response (61)(62)(63), and thus may not respond as effectively as other neurons to an overload of the protein homeostasis system (64). As a result, motor neurons may be particularly vulnerable to dysregulation of protein homeostasis, a conclusion that provides a possible explanation of the highly heterogeneous nature of inclusions in ALS, where only a small set of proteins associated with protein degradation (including OPTN, SQSTM1, UBC, and UBQLN2) are present in all three categories of inclusions.…”

Section: Discussion Spinal Motor Neuron Vulnerability To Als Is Linkementioning

confidence: 99%

Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS

Ciryam

Lambert-Smith

Bean

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Amyotrophic lateral sclerosis (ALS) is a heterogeneous degenerative motor neuron disease linked to numerous genetic mutations in apparently unrelated proteins. These proteins, including SOD1, TDP-43, and FUS, are highly aggregation-prone and form a variety of intracellular inclusion bodies that are characteristic of different neuropathological subtypes of the disease. Contained within these inclusions are a variety of proteins that do not share obvious characteristics other than coaggregation. However, recent evidence from other neurodegenerative disorders suggests that diseaseaffected biochemical pathways can be characterized by the presence of proteins that are supersaturated, with cellular concentrations significantly greater than their solubilities. Here, we show that the proteins that form inclusions of mutant SOD1, TDP-43, and FUS are not merely a subset of the native interaction partners of these three proteins, which are themselves supersaturated. To explain the presence of coaggregating proteins in inclusions in the brain and spinal cord, we observe that they have an average supersaturation even greater than the average supersaturation of the native interaction partners in motor neurons, but not when scores are generated from an average of other human tissues. These results suggest that inclusion bodies in various forms of ALS result from a set of proteins that are metastable in motor neurons, and thus prone to aggregation upon a disease-related progressive collapse of protein homeostasis in this specific setting.protein aggregation | protein misfolding | protein homeostasis | supersaturation | motor neuron disease

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Section: Discussion Spinal Motor Neuron Vulnerability To Als Is Linkementioning

confidence: 99%

Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS

Ciryam

Lambert-Smith

Bean

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…S7). Nevertheless, assessing the effect of specific GM3 isoforms in newly developed in vitro human cell models of ALS (40)(41)(42) has the potential to validate the merit of altering GM3 levels to treat the human condition.…”

Section: Discussionmentioning

confidence: 99%

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Dodge

Treleaven

Pacheco

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

108

141

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Recent genetic evidence suggests that aberrant glycosphingolipid metabolism plays an important role in several neuromuscular diseases including hereditary spastic paraplegia, hereditary sensory neuropathy type 1, and non-5q spinal muscular atrophy. Here, we investigated whether altered glycosphingolipid metabolism is a modulator of disease course in amyotrophic lateral sclerosis (ALS). Levels of ceramide, glucosylceramide, galactocerebroside, lactosylceramide, globotriaosylceramide, and the gangliosides GM3 and GM1 were significantly elevated in spinal cords of ALS patients. Moreover, enzyme activities (glucocerebrosidase-1, glucocerebrosidase-2, hexosaminidase, galactosylceramidase, α-galactosidase, and β-galactosidase) mediating glycosphingolipid hydrolysis were also elevated up to threefold. Increased ceramide, glucosylceramide, GM3, and hexosaminidase activity were also found in SOD1 G93A mice, a familial model of ALS. Inhibition of glucosylceramide synthesis accelerated disease course in SOD1 G93A mice, whereas infusion of exogenous GM3 significantly slowed the onset of paralysis and increased survival. Our results suggest that glycosphingolipids are likely important participants in pathogenesis of ALS and merit further analysis as potential drug targets.A myotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective loss of motor neurons (MNs) within the CNS. Although our understanding of the genetic basis of ALS has advanced greatly in recent years (1), the adverse biological processes that converge on the neuromuscular axis to drive both MN death and neuropathological features in additional cell types remain largely unknown. Glycosphingolipids (GSLs) are a heterogeneous group of membrane lipids formed through the covalent linkage of a glycan moiety to ceramide (Cer; see SI Appendix, Fig. S1 for an overview of GSL metabolism). Glucosylceramide (GlcCer) and galactosylceramide (GalCer) are GSLs with a single sugar residue: glucose and galactose respectively. The successive addition of galactose and sialic acid moieties to GlcCer results in the synthesis of gangliosides (e.g., GM3, GM2, and GM1) (2). GSLs are especially abundant in the CNS and have bioactive roles in metabolism, growth factor signaling, oligodendrocyte differentiation, neuroinflammation, angiogenesis, and pathways of cell death (2-9)-all of which are thought to participate in ALS disease pathogenesis.Several lines of evidence suggest that aberrant changes in GSL homeostasis may contribute to disease pathogenesis in ALS. Evidence includes the detection of unique gangliosides (10), high titer serum auto-antibodies to GM2 and GM1 (11,12), and elevated GM2 levels within the motor cortex of ALS patients (13). Furthermore, a number of neuromuscular diseases are associated with mutations in genes that regulate the metabolism of Cer and GSLs. For example, hereditary sensory neuropathy type I (HSNT1), a disease that features dorsal root ganglion cell and MN degeneration, is attributed to mutations in serine...

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“…This was evident in wholegenome analysis of engineered human stem cells from multiple laboratories, which uncovered few off-target effects (Duan et al 2014;Kiskinis et al 2014;Smith et al 2014;Suzuki et al 2014;Veres et al 2014). Recent work has shown that truncating the 59 end of the gRNA, where mismatches with the genomic target sequence are tolerated, further increases specificity .…”

Section: Making the Cut: Comparing The Crispr-cas9 System With Zfns Amentioning

confidence: 99%

A CRISPR view of development

et al. 2014

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The CRISPR (clustered regularly interspaced short palindromic repeat)–Cas9 (CRISPR-associated nuclease 9) system is poised to transform developmental biology by providing a simple, efficient method to precisely manipulate the genome of virtually any developing organism. This RNA-guided nuclease (RGN)-based approach already has been effectively used to induce targeted mutations in multiple genes simultaneously, create conditional alleles, and generate endogenously tagged proteins. Illustrating the adaptability of RGNs, the genomes of >20 different plant and animal species as well as multiple cell lines and primary cells have been successfully modified. Here we review the current and potential uses of RGNs to investigate genome function during development.

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Pathways Disrupted in Human ALS Motor Neurons Identified through Genetic Correction of Mutant SOD1

Cited by 33 publications

References 0 publications

Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS

Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

A CRISPR view of development

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