Different Impact of ALS on Laminin Isoforms in Human Extraocular Muscles versus Limb Muscles

Liu, Jing‐Xia; Brännström, Thomas; Andersen, Peter M.; Domellöf, Fátima Pedrosa

doi:10.1167/iovs.10-7132

Cited by 24 publications

(30 citation statements)

References 51 publications

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“…This study is important because changes in laminin chains could be one of the causes associated with the NMJ degeneration seen in ALS, which may subsequently affects the progression of the disease. This is supported by the study of Liu et al (2011) which demonstrated altered laminins expression in ALS donors suggesting the potential involvement of laminins in NMJ degeneration of ALS (see Section 1.3; Dying-backward hypothesis in amyotrophic lateral sclerosis).…”

Section: The Involvement Of Transactive Response Dna Binding Protein mentioning

confidence: 64%

“…A recent study by Liu et al (2011) found absent expression of laminin-α4 at the NMJs of limb muscles in ALS patients. This novel finding highlighted the potential involvement of laminins in ALS disease states.…”

Section: Introductionmentioning

confidence: 92%

“…Indeed, the study by Liu et al (2011) found missing expression of laminin-α4 at the NMJs of limb muscles and laminins-α2 and -β2 at the NMJs of extraocular muscles in ALS donors. In order to investigate whether the decreased expression of laminins-α2 and -β2 at the NMJ was the result of denervation, the same study conducted a further observation on the distribution of synaptophysin and neurofilament, which are markers for nerve terminal and motor axons respectively, and found that most NMJs were strongly labelled with the respective markers indicating normal innervation.…”

Section: Dying-backward Hypothesis In Amyotrophic Lateral Sclerosismentioning

confidence: 98%

“…In ALS disease, missing expression of laminin-α4 was found at the NMJs of limb muscles in ALS donors highlighting the possible involvement of this laminin in the progression or initiation of this disease (Liu et al, 2011). This change in laminin-α4 expression in ALS disease was only recently noted and has yet to be investigated sufficiently.…”

Section: Rationalementioning

confidence: 99%

“…One particular study showed loss of laminin-α4 expression at the NMJs of limb muscles in human ALS donors (Liu et al, 2011), suggesting the possible involvement of laminins in the NMJ degeneration in ALS disease. This led to my interest in investigating the involvement of laminins in TDP43 Q331K mouse model of ALS during presymptomatic (3MO) and onset stages (10MO).…”

Section: Interaction Of Laminin Chains With Pre-and Postsynaptic Recementioning

confidence: 99%

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The role of synaptic laminins-α4 and -β2 in maturation and maintenance of the neuromuscular synapse

Lee¹

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The proper development, maturation and maintenance of the neuromuscular junction (NMJ) are critical for ensuring efficient neurotransmission. Proteins found within the basal lamina of the synaptic cleft, namely the laminins family, are heavily involved in maintaining normal structure and function of the NMJ. In particular, individual laminin chains such as laminin-β2, -α4 and -α5 play essential roles in organisation and maintenance of the NMJ. These laminin chains interact together to form three synapse specific laminin heterotrimers; laminin-221 (α2β2γ1), laminin-421 (α4β2γ1) and laminin-521 (α5β2γ1).Laminin-β2 is the common laminin chain found in each of these synapse specific laminin heterotrimers. In-vitro it has been shown to play a key role in the organisation of the presynaptic elements at the NMJ via its interaction and clustering of the N-and P/Q-type voltage-gated calciums (VGCCs). During development of the NMJ, both N-and P/Q-type VGCCs are involved in mediating neurotransmitter release. As the NMJ matures, P/Q-type becomes the dominant channel involved in release while N-type takes on the role of fine-tuning calcium influx. Laminin-α4, on the other hand, ensures proper alignment of presynaptic active zones to postjunctional folds at the NMJ, with its loss resulting in misalignment of these specialisations. Furthermore, this laminin chain has been shown to be involved in the maintenance of the NMJ with the observation of premature ageing features at 6 months of age (6MO) in laminin-α4 deficient mice (lama4 NMJs.In conclusion, this thesis has identified the significant roles laminins-α4 and -β2 play at the NMJ during development, maturation and maintenance. Results suggest that laminin-β2 is not only an important regulator of the presynaptic maturation through the switching of VGCCs and clustering of P/Q-type VGCCs, but also equally important for maturation of the postsynaptic apparatus. Ipropose that laminin-β2 is important for the maturation of each component at the NMJ. The altered responses in transmission properties presented by aged wild-type NMJs which resembled adult lama4 -/-, preceded by altered expression of laminin-α4 chain, strongly suggest that laminin-α4 is not only important for maintaining proper alignment of pre-to postsynaptic NMJ, but also essentially important for maintaining a healthy adult NMJ. Finally, I observed early alterations in expression of laminin-α4 at the NMJs in diseased mouse model of ALS prior to any appearance of neuromotor impairment, suggesting a potential involvement of laminins in NMJ degeneration associated with neuromuscular disorders such as ALS.ii

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Section: The Involvement Of Transactive Response Dna Binding Protein mentioning

confidence: 64%

Section: Introductionmentioning

confidence: 92%

Section: Dying-backward Hypothesis In Amyotrophic Lateral Sclerosismentioning

confidence: 98%

Section: Rationalementioning

confidence: 99%

Section: Interaction Of Laminin Chains With Pre-and Postsynaptic Recementioning

confidence: 99%

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The role of synaptic laminins-α4 and -β2 in maturation and maintenance of the neuromuscular synapse

Lee¹

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Extraocular Muscles Response to Neuromuscular Diseases and Specific Pathologies

Domellöf

2012

Craniofacial Muscles

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Pathology of the Optic Nerve and Extraocular Muscle

Chévez-Barrios

Cykowski

2022

Albert and Jakobiec's Principles and Practice of Ophthalmology

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Different Impact of ALS on Laminin Isoforms in Human Extraocular Muscles versus Limb Muscles

Abstract: The present study showed distinct impact of ALS on EOMs compared with limb muscles. The EOMs maintained a normal laminin composition in their NMJs, which may be instrumental for the fact that they are not typically affected in ALS.

Cited by 24 publications

References 51 publications

The role of synaptic laminins-α4 and -β2 in maturation and maintenance of the neuromuscular synapse

The role of synaptic laminins-α4 and -β2 in maturation and maintenance of the neuromuscular synapse

Extraocular Muscles Response to Neuromuscular Diseases and Specific Pathologies

Pathology of the Optic Nerve and Extraocular Muscle

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