Abstract
In the present review we discuss the potential involvement of adenosinergic signaling, in particular the role of adenosine receptors, in amyotrophic lateral sclerosis (ALS). Though the literature on this topic is not abundant, the information so far available on adenosine receptors in animal models of ALS highlights the interest to continue to explore the role of these receptors in this neurodegenerative disease. Indeed, all motor neurons affected in ALS are responsive to adenosine receptor ligands but interestingly, there are alterations in pre-symptomatic or early symptomatic stages that mirror those in advanced disease stages. Information starts to emerge pointing toward a beneficial role of A2A receptors (A2AR), most probably at early disease states, and a detrimental role of caffeine, in clear contrast with what occurs in other neurodegenerative diseases. However, some evidence also exists on a beneficial action of A2AR antagonists. It may happen that there are time windows where A2AR prove beneficial and others where their blockade is required. Furthermore, the same changes may not occur simultaneously at the different synapses. In line with this, it is not fully understood if ALS is a dying back disease or if it propagates in a centrifugal way. It thus seems crucial to understand how motor neuron dysfunction occurs, how adenosine receptors are involved in those dysfunctions and whether the early changes in purinergic signaling are compensatory or triggers for the disease. Getting this information is crucial before starting the design of purinergic based strategies to halt or delay disease progression.
Highlights
In the present review, we will address the potential role of adenosine on amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease
Having studied the action of adenosine for more than 40 years, using the neuromuscular junction as a model, and considering that this simple synaptic model could be as a sort of key (Arbour et al, 2017) to investigate novel approaches for disease therapy, and that this particular synapse is compromised in ALS, we hypothesized (Nascimento et al, 2014, 2015) that ALS progression could be accompanied by changes in the functioning of adenosine A1R and A2A receptors (A2AR), the two high affinity adenosine receptors known to be expressed at motor nerve endings (Correia-de-Sá and Ribeiro, 1994)
We found that at the pre-symptomatic stage the A2AR-mediated presynaptic facilitatory action on neuromuscular transmission is exacerbated, whereas in the early symptomatic phase, this excitatory action disappears, indicating that that A2AR function changes upon ALS progression
Summary
About 20% of fALS are caused by a missense mutation in SOD1 gene, encoding for the Cu/Zn superoxide dismutase 1 enzyme This finding led to the first and most used rodent model for ALS, the SOD1G93A mouse, which in the symptomatic phase recapitulate most features of the disease, including neuromuscular dysfunction (Naumenko et al, 2011). Mutations in the gene coding for a nuclear protein, TAR DNAbinding protein-43 are frequent in fALS (Leblond et al, 2014) This protein has several functions in regulation of gene expression, which indicates a clear dysfunction at the level of the neuronal soma in some forms of ALS. In this review we will critically analyze data so far available
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