Neuronal Matrix Metalloproteinase-9 Is a Determinant of Selective Neurodegeneration

Kaplan, Artem; Spiller, Krista; Towne, Chris; Kanning, Kevin C.; Choe, Ginn T.; Geber, Adam; Akay, Turgay; Aebischer, Patrick; Henderson, Christopher E.

doi:10.1016/j.neuron.2013.12.009

Cited by 267 publications

(346 citation statements)

References 48 publications

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“…In sharp contrast, none of the delayed-firing motoneurons expresses ERR␤, suggesting that they are F-type motoneurons, and the largest ones, i.e., those with the largest rheobase, do express chondrolectin. In the same line, we showed that MMP-9, known to be selectively expressed by the most vulnerable motoneurons in amyotrophic lateral sclerosis, i.e., those innervating the fast-contracting and fatigable motor units (Kaplan et al 2014), is expressed in the largest delayedfiring motoneurons and not in the immediate-firing ones.…”

Section: Leroy F Lamotte D'incamps B Zytnicki Dmentioning

confidence: 64%

Potassium currents dynamically set the recruitment and firing properties of F-type motoneurons in neonatal mice

Leroy

d’Incamps

Zytnicki

2015

Journal of Neurophysiology

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114: 1963-1973, 2015. First published August 12, 2015 doi:10.1152/jn.00193.2015.-In neonatal mice, fast-and slow-type motoneurons display different patterns of discharge. In response to a long liminal current pulse, the discharge is delayed up to several seconds in fast-type motoneurons and their firing frequency accelerates. In contrast, slow-type motoneurons discharge immediately, and their firing frequency decreases at the beginning of the pulse. Here, we identify the ionic currents that underlie the delayed firing of fast-type motoneurons. We find that the firing delay is caused by a combination of an A-like potassium current that transiently suppresses firing on a short time scale and a slowlyinactivating potassium current that inhibits the discharge over a much longer time scale. We then show how these intrinsic currents dynamically shape the discharge threshold and the frequency-input function of fast-type motoneurons. These currents contribute to the orderly recruitment of motoneurons in neonates and might play a role in the postnatal maturation of motor units.spinal motoneurons subtypes; potassium currents; functional properties

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Section: Leroy F Lamotte D'incamps B Zytnicki Dmentioning

confidence: 64%

Potassium currents dynamically set the recruitment and firing properties of F-type motoneurons in neonatal mice

Leroy

d’Incamps

Zytnicki

2015

Journal of Neurophysiology

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“…4I), raising the question of whether MN resistance is linked to the absence of sensory input. Gene expression in ALS-resistant MNs is distinct from that of vulnerable MNs (42), and one differentially expressed gene (sema3e) is a known repellent for sensory afferent input (43,44). These findings raise the possibility that molecular distinctions between vulnerable and resistant MNs may influence MN survival in ALS through changes in synaptic connectivity and circuit function.…”

Section: Discussionmentioning

confidence: 99%

Gamma motor neurons survive and exacerbate alpha motor neuron degeneration in ALS

Lalancette–Hébert

Sharma

Lyashchenko

et al. 2016

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

106

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The molecular and cellular basis of selective motor neuron (MN) vulnerability in amyotrophic lateral sclerosis (ALS) is not known. In genetically distinct mouse models of familial ALS expressing mutant superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS), we demonstrate selective degeneration of alpha MNs (α-MNs) and complete sparing of gamma MNs (γ-MNs), which selectively innervate muscle spindles. Resistant γ-MNs are distinct from vulnerable α-MNs in that they lack synaptic contacts from primary afferent (I A ) fibers. Elimination of these synapses protects α-MNs in the SOD1 mutant, implicating this excitatory input in MN degeneration. Moreover, reduced I A activation by targeted reduction of γ-MNs in SOD1G93A mutants delays symptom onset and prolongs lifespan, demonstrating a pathogenic role of surviving γ-MNs in ALS. This study establishes the resistance of γ-MNs as a general feature of ALS mouse models and demonstrates that synaptic excitation of MNs within a complex circuit is an important determinant of relative vulnerability in ALS.ALS | motor neuron disease | gamma motor neuron | fusimotor A myotrophic lateral sclerosis (ALS) is a fatal disorder characterized by selective motor neuron (MN) degeneration in the brain and spinal cord (1). Not all MN subtypes are equally vulnerable in ALS, and specific subpopulations of MNs, including neurons in the oculomotor and Onuf's nuclei, are preserved even at late stages of disease (2-8). The sparing of these motor pools in ALS is complete, but within the motor pools that are affected the degree to which distinct functional subtypes of MNs are vulnerable varies: fast-fatigable motor neurons are the first to degenerate in ALS patients (9) and in mutant SOD1 mice (10, 11), followed by fatigue-resistant motor units, whereas slow motor units are preserved until late in the course of the disease (12). The reason for the selective vulnerability of distinct subpopulations of MNs in ALS is not known, but factors that determine the unique features of individual MN subtypes, including their size, morphology, and membrane properties, may play a role. In addition, the factors that influence MN vulnerability in ALS may relate to the organization and function of synaptic inputs on each MN subtype that regulate MN activity and control motor output. How the connectivity of MNs within complex motor circuits influences their relative vulnerability in ALS is not known.Extraocular muscles composed of multiple (fast-, intermediate-, and slow-twitch) fiber types (13) and innervated by ALS

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“…patients and SOD1 G93A mice. An increase in GM3 may also potentially slow disease by promoting oligodendrocyte differentiation (6), which is adversely affected in ALS mice (37), or by inhibiting the activation of matrix metalloproteinase-9 (38), which is expressed at high levels in those MNs most vulnerable in ALS (39). Interestingly, gene expression analysis studies carried out in ALS mice have shown that HEX (an enzyme that metabolizes GM2 to GM3) mRNA level is up-regulated in MNs before and during overt signs of disease (21,22).…”

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.

111

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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Neuronal Matrix Metalloproteinase-9 Is a Determinant of Selective Neurodegeneration

Cited by 267 publications

References 48 publications

Potassium currents dynamically set the recruitment and firing properties of F-type motoneurons in neonatal mice

Potassium currents dynamically set the recruitment and firing properties of F-type motoneurons in neonatal mice

Gamma motor neurons survive and exacerbate alpha motor neuron degeneration in ALS

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

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