Absence of acetylcholinesterase at the neuromuscular junctions of perlecan-null mice

Arikawa‐Hirasawa, Eri; Rossi, Susana G.; Rotundo, Richard L.; Yamada, Yoshihiko

doi:10.1038/nn801

Cited by 153 publications

(95 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Later studies showed that exogenously added asymmetric AChE associated specifically with nerve-muscle contact sites in a heparin-sensitive manner (8), suggesting that HSPGs would define its localization at the neuromuscular junction. Perlecan, a basal lamina HSPG, has been proposed as the receptor of collagen-tailed AChE (9), consistent with the recent finding that AChE is not accumulated at the neuromuscular junction in perlecan-null mice (10).…”

supporting

confidence: 82%

Two Different Heparin-binding Domains in the Triple-helical Domain of ColQ, the Collagen Tail Subunit of Synaptic Acetylcholinesterase

Deprez

Inestrosa

Krejci

2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

ColQ, the collagen tail subunit of asymmetric acetylcholinesterase, is responsible for anchoring the enzyme at the vertebrate synaptic basal lamina by interacting with heparan sulfate proteoglycans. To get insights about this function, the interaction of ColQ with heparin was analyzed. For this, heparin affinity chromatography of the complete oligomeric enzyme carrying different mutations in ColQ was performed. Results demonstrate that only the two predicted heparin-binding domains present in the collagen domain of ColQ are responsible for heparin interaction. Despite their similarity in basic charge distribution, each heparin-binding domain had different affinity for heparin. This difference is not solely determined by the number or nature of the basic residues conforming each site, but rather depends critically on local structural features of the triple helix, which can be influenced even by distant regions within ColQ. Thus, ColQ possesses two heparinbinding domains with different properties that may have non-redundant functions. We hypothesize that these binding sites coordinate acetylcholinesterase positioning within the organized architecture of the neuromuscular junction basal lamina.At vertebrate cholinergic synapses, acetylcholinesterase (AChE) 1 rapidly hydrolyzes the neurotransmitter acetylcholine, thereby terminating synaptic transmission. This key function does not only require a high catalytic turnover number but also a strategic positioning of the enzyme. This is achieved by the association of AChE catalytic subunits with structural subunits that bring them to the site of action. In the case of asymmetric AChE, the collagen ColQ is responsible for the localization of the enzyme at the vertebrate neuromuscular junction. Inactivation of the ColQ gene in mice or mutations in the human ColQ gene result in the absence of enzyme accumulation at the neuromuscular junction and are the cause of a congenital myasthenic syndrome (type 1c) (1, 2).As found in other collagens, ColQ contains a central triplehelical domain surrounded by non-collagenous N-and C-terminal domains (Fig. 1A). Each N-terminal domain organizes an AChE tetramer, so the triple-helical structure generates an A 12 or asymmetric AChE form with 12 catalytic subunits (3, 4). The collagen domain is characterized by Gly-Xaa-Yaa repeats and a high proportion of the stabilizing proline and hydroxyproline residues. The C-terminal domain is divided into a proline-rich region, important for triple-helix formation (5), and a cysteinerich region probably involved in the anchorage of AChE at the neuromuscular junction, since mutations in this region prevent the accumulation of AChE in congenital myasthenic syndrome type 1c patients (2).Heparan sulfate proteoglycans (HSPGs) have been implicated in the anchorage of asymmetric AChE to the synaptic basal lamina by interacting with ColQ through their heparan sulfate (HS) chains. This was proposed after showing that AChE could be specifically solubilized from the tissue with heparinase as well as with HS and ...

show abstract

supporting

confidence: 82%

Two Different Heparin-binding Domains in the Triple-helical Domain of ColQ, the Collagen Tail Subunit of Synaptic Acetylcholinesterase

Deprez

Inestrosa

Krejci

2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Perlecan Null allele: embryonic lethal (E10-12); developmental angiogenesis altered in zebrafish ); high incidence of malformations of the cardiac outflow tract, lack of well-defined spiral endocardial ridges (Costell et al 2002); lower amounts of collagen IV and laminins in embryonic hearts, reduced function in infarcted hearts from heterozygous mice (Sasse et al 2008); absence of acetylcholinesterase at the neuromuscular junctions (Arikawa-Hirasawa et al 2002); cephalic and skeletal abnormalities (Arikawa-Hirasawa et al 1999); cerebral ectopias, exencephaly (Giró s et al 2007); increased cross-sectional area of myosin heavy chain type IIb fibers in the tibialis anterior muscle (Xu et al 2010b); diminished osteocyte canalicular pericellular area (Thompson et al 2011). Exon 3 deletion (Hspg2 3/3 ) viable: proteinuria after protein loading (Morita et al 2005); monocyte/macrophage influx impaired in Hspg2 3/3 Col18a1 2/ -mice in a model of renal ischemia/reperfusion (Celie et al 2007).…”

Section: Hspg2mentioning

confidence: 99%

Heparan Sulfate Proteoglycans

Sarrazin¹,

Lamanna²,

Esko

2011

Cold Spring Harbor Perspectives in Biology

1,219

1,238

View full text Add to dashboard Cite

“…Perlecan is a major component of basement membranes and plays a critical role at the neuromuscular junction by anchoring AChE to the synaptic basement membrane. 13,31 Perlecan deficiency results in Schwartz-Jampel syndrome, a human recessive disorder with peripheral nerve hyperexcitability. 32,33 We recently demonstrated abnormal neuromuscular transmission with muscle fatigability (tetanic fade) at low frequency of nerve stimulation in perlecan-deficient muscle.…”

Section: Beneficial Effect Of Lt On Fatigue Resistance In Thementioning

confidence: 99%

Effect of locomotor training on muscle performance in the context of nerve–muscle communication dysfunction

et al. 2012

View full text Add to dashboard Cite

Introduction: The effects of locomotor training (LT) on skeletal muscle after peripheral nerve injury and acetylcholinesterase deficiency are not well documented. Methods: We determined the effects of LT on mouse soleus muscle performance after sciatic nerve transection with excision (full and permanent denervation), nerve transection (partial functional reinnervation), nerve crush (full denervation with full functional reinnervation), and acetylcholinesterase deficiency (alteration in neuromuscular junction functioning). Results: We found no significant effect of LT on the recovery of soleus muscle weight, maximal force in response to muscle stimulation, and fatigue resistance after nerve transection with or without excision. However, LT significantly increased soleus muscle fatigue resistance after nerve crush and acetylcholinesterase deficiency. Moreover, hindlimb immobilization significantly aggravated the deficit in soleus muscle maximal force production and atrophy after nerve crush. Conclusions: LT is beneficial, and reduced muscle use is detrimental for intrinsic muscle performance in the context of disturbed nerve-muscle communication.

show abstract

Absence of acetylcholinesterase at the neuromuscular junctions of perlecan-null mice

Cited by 153 publications

References 36 publications

Two Different Heparin-binding Domains in the Triple-helical Domain of ColQ, the Collagen Tail Subunit of Synaptic Acetylcholinesterase

Two Different Heparin-binding Domains in the Triple-helical Domain of ColQ, the Collagen Tail Subunit of Synaptic Acetylcholinesterase

Heparan Sulfate Proteoglycans

Effect of locomotor training on muscle performance in the context of nerve–muscle communication dysfunction

Contact Info

Product

Resources

About