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Endplate denervation correlates with Nogo-A muscle expression in amyotrophic lateral sclerosis patients.

Bruneteau G, Bauché S, Gonzalez de Aguilar JL, Brochier G, Mandjee N, Tanguy ML, Hussain G, Behin A, Khiami F, Sariali E, Hell-Remy C, Salachas F, Pradat PF, Lacomblez L, Nicole S, Fontaine B, Fardeau M, Loeffler JP, Meininger V, Fournier E, Koenig J, Hantaï D - Ann Clin Transl Neurol (2015)

Bottom Line: Finally, high-level expression of Nogo-A in muscle was significantly associated with higher extent of NMJ denervation and negative functional outcome.Our results support the hypothesis that morphological alterations of NMJs are present from early-stage disease and may significantly contribute to functional motor impairment in ALS patients.Muscle expression of Nogo-A is associated with NMJ denervation and thus constitutes a therapeutic target to slow disease progression.

View Article: PubMed Central - PubMed

Affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France ; APHP, Hôpital Pitié-Salpêtrière, Département des Maladies du Système Nerveux, Centre référent SLA Paris, France ; APHP, INSERM, ICM, Centre d'Investigation Clinique Pitié Neurosciences, CIC-1422, Département des Maladies du Système Nerveux, Hôpital Pitié-Salpêtrière Paris, France.

ABSTRACT

Objective: Data from mouse models of amyotrophic lateral sclerosis (ALS) suggest early morphological changes in neuromuscular junctions (NMJs), with loss of nerve-muscle contact. Overexpression of the neurite outgrowth inhibitor Nogo-A in muscle may play a role in this loss of endplate innervation.

Methods: We used confocal and electron microscopy to study the structure of the NMJs in muscle samples collected from nine ALS patients (five early-stage patients and four long-term survivors). We correlated the morphological results with clinical and electrophysiological data, and with Nogo-A muscle expression level.

Results: Surface electromyography assessment of neuromuscular transmission was abnormal in 3/9 ALS patients. The postsynaptic apparatus was morphologically altered for almost all NMJs (n = 430) analyzed using confocal microscopy. 19.7% of the NMJs were completely denervated (fragmented synaptic gutters and absence of nerve terminal profile). The terminal axonal arborization was usually sparsely branched and 56.8% of innervated NMJs showed a typical reinnervation pattern. Terminal Schwann cell (TSC) morphology was altered with extensive cytoplasmic processes. A marked intrusion of TSCs in the synaptic cleft was seen in some cases, strikingly reducing the synaptic surface available for neuromuscular transmission. Finally, high-level expression of Nogo-A in muscle was significantly associated with higher extent of NMJ denervation and negative functional outcome.

Interpretation: Our results support the hypothesis that morphological alterations of NMJs are present from early-stage disease and may significantly contribute to functional motor impairment in ALS patients. Muscle expression of Nogo-A is associated with NMJ denervation and thus constitutes a therapeutic target to slow disease progression.

No MeSH data available.


Related in: MedlinePlus

Electron microscopy view showing an interposition of the terminal Schwann cell (TSC) between the axon terminal and the postsynaptic muscle membrane. (A, B) The membrane of the TSC (star) invades the synaptic cleft (arrowhead) and encases the nerve terminal (N). Secondary synaptic clefts are maintained (white arrow). Note in (B) that the area of the muscle postsynaptic membrane facing the residual part of the nerve terminal (black arrow), available for neurotransmission, is very narrow. Scale bar, 2 μm.
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fig05: Electron microscopy view showing an interposition of the terminal Schwann cell (TSC) between the axon terminal and the postsynaptic muscle membrane. (A, B) The membrane of the TSC (star) invades the synaptic cleft (arrowhead) and encases the nerve terminal (N). Secondary synaptic clefts are maintained (white arrow). Note in (B) that the area of the muscle postsynaptic membrane facing the residual part of the nerve terminal (black arrow), available for neurotransmission, is very narrow. Scale bar, 2 μm.

Mentions: Using confocal microscopy, we analyzed the TSC morphology of 51 NMJs (Table2, Fig.4). Most of the TSCs were abnormal with extensive cytoplasmic processes. On average, TSCs extended 2.22 processes and contacted 1.90 distinct postsynaptic elements. TSC alterations were similar in both ALS groups. On electron micrographs, TSCs normally “capped” the nerve terminal in some NMJs (Fig.2B–D), but in others a marked interposition of the TSC between the axon terminal and the postsynaptic membrane could be observed, which was sometimes so pronounced that only a small part of the synaptic surface was accessible for neuromuscular transmission (Fig.5). Multiple layers of TSC basal lamina were often visible near the primary synaptic cleft (Fig.2B).


Endplate denervation correlates with Nogo-A muscle expression in amyotrophic lateral sclerosis patients.

Bruneteau G, Bauché S, Gonzalez de Aguilar JL, Brochier G, Mandjee N, Tanguy ML, Hussain G, Behin A, Khiami F, Sariali E, Hell-Remy C, Salachas F, Pradat PF, Lacomblez L, Nicole S, Fontaine B, Fardeau M, Loeffler JP, Meininger V, Fournier E, Koenig J, Hantaï D - Ann Clin Transl Neurol (2015)

Electron microscopy view showing an interposition of the terminal Schwann cell (TSC) between the axon terminal and the postsynaptic muscle membrane. (A, B) The membrane of the TSC (star) invades the synaptic cleft (arrowhead) and encases the nerve terminal (N). Secondary synaptic clefts are maintained (white arrow). Note in (B) that the area of the muscle postsynaptic membrane facing the residual part of the nerve terminal (black arrow), available for neurotransmission, is very narrow. Scale bar, 2 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4402082&req=5

fig05: Electron microscopy view showing an interposition of the terminal Schwann cell (TSC) between the axon terminal and the postsynaptic muscle membrane. (A, B) The membrane of the TSC (star) invades the synaptic cleft (arrowhead) and encases the nerve terminal (N). Secondary synaptic clefts are maintained (white arrow). Note in (B) that the area of the muscle postsynaptic membrane facing the residual part of the nerve terminal (black arrow), available for neurotransmission, is very narrow. Scale bar, 2 μm.
Mentions: Using confocal microscopy, we analyzed the TSC morphology of 51 NMJs (Table2, Fig.4). Most of the TSCs were abnormal with extensive cytoplasmic processes. On average, TSCs extended 2.22 processes and contacted 1.90 distinct postsynaptic elements. TSC alterations were similar in both ALS groups. On electron micrographs, TSCs normally “capped” the nerve terminal in some NMJs (Fig.2B–D), but in others a marked interposition of the TSC between the axon terminal and the postsynaptic membrane could be observed, which was sometimes so pronounced that only a small part of the synaptic surface was accessible for neuromuscular transmission (Fig.5). Multiple layers of TSC basal lamina were often visible near the primary synaptic cleft (Fig.2B).

Bottom Line: Finally, high-level expression of Nogo-A in muscle was significantly associated with higher extent of NMJ denervation and negative functional outcome.Our results support the hypothesis that morphological alterations of NMJs are present from early-stage disease and may significantly contribute to functional motor impairment in ALS patients.Muscle expression of Nogo-A is associated with NMJ denervation and thus constitutes a therapeutic target to slow disease progression.

View Article: PubMed Central - PubMed

Affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France ; APHP, Hôpital Pitié-Salpêtrière, Département des Maladies du Système Nerveux, Centre référent SLA Paris, France ; APHP, INSERM, ICM, Centre d'Investigation Clinique Pitié Neurosciences, CIC-1422, Département des Maladies du Système Nerveux, Hôpital Pitié-Salpêtrière Paris, France.

ABSTRACT

Objective: Data from mouse models of amyotrophic lateral sclerosis (ALS) suggest early morphological changes in neuromuscular junctions (NMJs), with loss of nerve-muscle contact. Overexpression of the neurite outgrowth inhibitor Nogo-A in muscle may play a role in this loss of endplate innervation.

Methods: We used confocal and electron microscopy to study the structure of the NMJs in muscle samples collected from nine ALS patients (five early-stage patients and four long-term survivors). We correlated the morphological results with clinical and electrophysiological data, and with Nogo-A muscle expression level.

Results: Surface electromyography assessment of neuromuscular transmission was abnormal in 3/9 ALS patients. The postsynaptic apparatus was morphologically altered for almost all NMJs (n = 430) analyzed using confocal microscopy. 19.7% of the NMJs were completely denervated (fragmented synaptic gutters and absence of nerve terminal profile). The terminal axonal arborization was usually sparsely branched and 56.8% of innervated NMJs showed a typical reinnervation pattern. Terminal Schwann cell (TSC) morphology was altered with extensive cytoplasmic processes. A marked intrusion of TSCs in the synaptic cleft was seen in some cases, strikingly reducing the synaptic surface available for neuromuscular transmission. Finally, high-level expression of Nogo-A in muscle was significantly associated with higher extent of NMJ denervation and negative functional outcome.

Interpretation: Our results support the hypothesis that morphological alterations of NMJs are present from early-stage disease and may significantly contribute to functional motor impairment in ALS patients. Muscle expression of Nogo-A is associated with NMJ denervation and thus constitutes a therapeutic target to slow disease progression.

No MeSH data available.


Related in: MedlinePlus