Neuromuscular Junction Dysfunction in Amyotrophic Lateral Sclerosis

Verma, Sagar; Khurana, Shiffali; Vats, Abhishek; Sahu, Bandana Kumari; Ganguly, Nirmal Kumar; Chakraborti, Pradip K.; Gourie-Devi, Mandaville; Taneja, Vibha

doi:10.1007/s12035-021-02658-6

Cited by 41 publications

(20 citation statements)

References 290 publications

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“…This is a fatal neurodegenerative disease that is usually detected in the eighth decade of life and is conventionally believed to originate in the motor neurons of the central nervous system (CNS) before proceeding to the skeletal muscle in an anterograde manner. However, more recently, it has been suggested that this disease may first manifest itself at the NMJ and propagate in a retrograde manner along the motor neurons’ axons in a “dying back” direction [ 12 , 13 , 14 , 15 , 16 , 17 ]. What is clearly known, however, is that the NMJ is affected by ALS, resulting in weakening and wasting of the skeletal muscle [ 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Adaptive Remodeling of the Neuromuscular Junction with Aging

Deschenes

Flannery

Hawbaker

et al. 2022

Cells

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Aging is associated with gradual degeneration, in mass and function, of the neuromuscular system. This process, referred to as “sarcopenia”, is considered a disease by itself, and it has been linked to a number of other serious maladies such as type II diabetes, osteoporosis, arthritis, cardiovascular disease, and even dementia. While the molecular causes of sarcopenia remain to be fully elucidated, recent findings have implicated the neuromuscular junction (NMJ) as being an important locus in the development and progression of that malady. This synapse, which connects motor neurons to the muscle fibers that they innervate, has been found to degenerate with age, contributing both to senescent-related declines in muscle mass and function. The NMJ also shows plasticity in response to a number of neuromuscular diseases such as amyotrophic lateral sclerosis (ALS) and Lambert-Eaton myasthenic syndrome (LEMS). Here, the structural and functional degradation of the NMJ associated with aging and disease is described, along with the measures that might be taken to effectively mitigate, if not fully prevent, that degeneration.

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Section: Introductionmentioning

confidence: 99%

Adaptive Remodeling of the Neuromuscular Junction with Aging

Deschenes

Flannery

Hawbaker

et al. 2022

Cells

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“…Studies in ALS patients have shown that there is an association between reduced numbers of Tregs and increased disease severity, progression, and survival [ 59 , 60 ]. Finally, alterations in the muscle and neuromuscular junction may also play a role in retrograde degeneration of the motoneuron [ 61 , 62 ], with changes in gene expression in the muscle being associated with disease progression [ 63 ]. Several mechanisms have been proposed, such as increased expression of proteins such as Nog-A that inhibit neuromuscular stabilization [ 64 ], satellite cell abnormalities [ 65 ], a reduction in trophic factors secreted by the muscle [ 66 ], or, more recently, the secretion of toxic exosomes [ 67 ].…”

Section: Some Aspects Of Als Disease Mechanisms Acted Upon By Therape...mentioning

confidence: 99%

Status of ALS Treatment, Insights into Therapeutic Challenges and Dilemmas

Khamaysa

2022

JPM

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Amyotrophic lateral sclerosis (ALS) is an extremely heterogeneous disease of motor neurons that eventually leads to death. Despite impressive advances in understanding the genetic, molecular, and pathological mechanisms of the disease, the only drug approved to date by both the FDA and EMA is riluzole, with a modest effect on survival. In this opinion view paper, we will discuss how to address some challenges for drug development in ALS at the conceptual, technological, and methodological levels. In addition, socioeconomic and ethical issues related to the legitimate need of patients to benefit quickly from new treatments will also be addressed. In conclusion, this brief review takes a more optimistic view, given the recent approval of two new drugs in some countries and the development of targeted gene therapies.

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“…Altough their role in the disease is still under investigation and many mechanistic aspects need to be clarified, as recently reviewed, dysfunctional and degenerating oligodendroglial cells and loss of terminal schwann cells seem to contribute to the ALS pathology, representing additional potential therapeutic targets for designing effective therapies [ 73 , 74 , 75 ]. Interestingly, the overexpression of Nrf2 in Schwann cells through targeted muscular injections or the activation of the Nrf2 signaling pathway by the oral administration diphenyl diselenide have been described to mediate sciatic nerve recovery in rat models of diabetic peripheral neuropathy [ 76 , 77 ].…”

Section: Role Of Glial Cells In Alsmentioning

confidence: 99%

Activation of the Nrf2 Pathway as a Therapeutic Strategy for ALS Treatment

Arslanbaeva

Bisaglia

2022

Molecules

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Amyotrophic lateral sclerosis is a progressive and fatal disease that causes motoneurons degeneration and functional impairment of voluntary muscles, with limited and poorly efficient therapies. Alterations in the Nrf2-ARE pathway are associated with ALS pathology and result in aberrant oxidative stress, making the stimulation of the Nrf2-mediated antioxidant response a promising therapeutic strategy in ALS to reduce oxidative stress. In this review, we first introduce the involvement of the Nrf2 pathway in the pathogenesis of ALS and the role played by astrocytes in modulating such a protective pathway. We then describe the currently developed activators of Nrf2, used in both preclinical animal models and clinical studies, taking into consideration their potentialities as well as the possible limitations associated with their use.

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Neuromuscular Junction Dysfunction in Amyotrophic Lateral Sclerosis

Cited by 41 publications

References 290 publications

Adaptive Remodeling of the Neuromuscular Junction with Aging

Adaptive Remodeling of the Neuromuscular Junction with Aging

Status of ALS Treatment, Insights into Therapeutic Challenges and Dilemmas

Activation of the Nrf2 Pathway as a Therapeutic Strategy for ALS Treatment

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