by Elena Moro
For November 2017, we have selected: Mittal S, Bjørnevik K, Im DS, et al. ß2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson’s disease. Science 2017;140:2295-2305.
Disturbed proteostasis of α-synuclein is now thought to play a critical role in the pathogenesis of Parkinson’s disease (PD). Physiological functions of this protein include synaptic transport as well as involvement in the metabolism of membrane phospholipids, and in the differentiation and survival of dopaminergic neurons. The strongest evidence for the pathogenic role of α-synuclein comes from mutations in the gene encoding the α-synuclein (SNCA gene) as well as duplication or triplication of this gene causing familial PD. Overexpression of the α-synuclein in neurons enables its aggregation even if the protein has a normal structure, thus suggesting that factors interfering with the expression of the α-synuclein can also contribute to the pathogenesis of sporadic PD. Therefore, agents able to reduce the SNCA gene transcription could have a neuroprotective effect, preventing or slowing down the PD pathology.
In this paper, Mittal et colleagues have used a singular approach to test the effectiveness of several compounds in altering SNCA gene expression in human neuronal cells. Following a four-stage study design (screening, replication, confirmation of transcript expression, and ELISA for protein quantification), they found four compounds able to significantly reduce SNCA gene expression. Three out of these four compounds were ß2-adrenoreceptor (ß2AR) agonists (metaproterenol, clenbuterol and salbutamol). These ß2AR agonists likely regulate endogenous SNCA gene expression in a dose- and time-dependent manner. The authors also found that ß2AR agonists could reduce nigral α-synuclein protein and mRNA level in rodent neurons. Conversely, ß2AR antagonists, such propranolol, increased both endogenous SNCA mRNA and α-synuclein protein levels. The ß2AR agonists seem to regulate SCNA gene transcription through the histone 3 lysine 27 acetylation (H3K27ac) across the SNCA promoter. Indeed, clenbuterol could decrease both H3K27ac levels and SNCA mRNA levels. In patient-derived cells carrying a SNCA gene triplication, ß2AR agonists significantly reduced endogenous SNCA mRNA expression.
Intriguingly, the authors were able to evaluate potential neuroprotective effects of salbutamol in humans using the Norwegian Prescription database (NorPD) that collects information about prescribed drugs in Norway since 2004 (more than 4 million Norwegians followed over 11 years). They found that salbutamol was linked to a decreased risk of developing PD (RR 0.66, 95% CI, 0.58-0.76), whereas propranolol was associated with an increased risk of PD (RR 2.20, 95%CI, 1.62-3.00).
“This is an interesting and intriguing paper, introducing a new approach to drug development in neurodegenerative disease”, says Pr. W. Poewe, Department of Neurology, Innsbruck, Austria. “The authors have shown that widely available compounds can have a role in the pathogenesis of PD by interacting positively or negatively with SNCA gene expression. This is very relevant since it can clarify the increased incidence of PD among certain populations. For instance, the association of essential tremor with PD could be explained by the possible role of propranolol, commonly used to treat essential tremor, in increasing the risk of PD.”
“This study has also the potential to expand research in compounds able to have a systemic or a more local effect in other neurological disorders, since a better understanding of their mechanism of action in the endogenous expression of disease-related genes will further open the way to tailored treatments.”, say Prof. E Ruzicka, Department of Neurology, Prague, Czech Republic.
“This study is an interesting example of translational research in neurodegenerative disorders. The potential beneficial effects of ß2AR agonists on nigral neurons and the expression of the SNCA gene encourage clinical research on the role of these drugs in preventing neurodegenerative disorders,” adds Pr. H Reichmann, Department of Neurology, Dresden, Germany.
“Nevertheless, the association between less risk of developing PD and the use of salbutamol as well as between increased risk of developing PD and the use of propranolol does not mean that there is a direct causative effect between drugs and disease”, says Prof. P. Taba, Department of Neurology, Tartu, Estonia. “These findings need to be confirmed by other epidemiological studies and more preclinical studies. Moreover, salbutamol can induce side effects, and by now it cannot be prescribed because of its potential neuroprotective role in PD.”
The other nominees for the November 2017 Paper of the month are:
- Mas J-L, Derumeaux G, Guillon B, et al., for the CLOSE Investigators. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med 2017;377:1011:1021. In this multicenter French trial, 663 patients with recent cryptogenetic stroke attributed to patent foramen ovale (PFO), with an associated atrial septal aneurysm or large interatrial shunt, were randomized to receive transcatheter PFO closure plus antiplatelets, antiplatelets alone, or anticoagulants. At a mean follow-up of about five years, patients who had PFO cloture and antiplatelet therapy had no stroke recurrence compared to the other two groups. However, PFO closure was associated with an increasedrisk of atrial fibrillation.
- Saver JL, Carroll JD, Thaler DE, et al., for the RESPECT Investigators. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med 2017;377:1022-1032. In this multicenter trial, 980 patients with patent foramen ovale (PFO) and cryptogenetic stroke were randomized to receive PFO closure or medical therapy (antiplatelets, antigoagulants). After a median of 5.9 years follow-up, patients with PFO closure had significant less recurrent ischemic stroke events.
- Sondergaard L, Kasner SE, Rhodes JF, et al., for the Gore REDUCE Clinical Study Investigators. Patent foramen ovale closure or antiplatelet therapy for cryptogenetic stroke. N Engl J Med 2017;377:1033-1042. In this multinational trial, 664 patients who had cryptogenetic stroke and patent foramen ovale (PFO) were randomized to receive PFO closure plus antiplatelet therapy or antiplatelet therapy alone. Within an average of 3-year follow-up, the risk of recurrent stroke was lower in patients with PFO closure plus antiplatelet therapy. Also in this study, PFO closure was associated with higher risk of atrial fibrillation.