Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, muscle atrophy and paralysis and for which no effective therapy is known.
The pathogenesis of ALS is not completely understood and while much controversy remains about its molecular and biochemical biology, there is increasing consensus that multiple mechanisms of injury converge as the disease progress.
Mounting evidence suggest that alterations of body metabolic homeostasis represent a crucial event in ALS onset or even a possible trigger of the pathology.
The hypothalamus and the Superchiasmatic nucleus (SNC) control circadian rhythm and metabolic changes, both of which are severely compromised in neurodegenerative disorders, such as ALS. The SNC synchronizes downstream peripheral clock, including the muscle one, to preserve tissue homeostasis, according to a functional hierarchy in response to environmental cues.
Here we propose to analyze the circadian rhythm in the hypothalamus and skeletal muscle of SOD1G93A mice, in pre-symptomatic phase and during disease progression, in order to verify whether the restoration of circadian metabolic homeostasis could represent a novel strategy to delay onset and attenuate disease progression.
Amyotrophic Lateral Sclerosis is a disease of proven genetic origin, appearing with a frequency of 1,5/100.000. Although during the last decades several efforts have been performed to understand the molecular mechanism underpinning ALS disease onset and progression, actually no therapy has been developed and, among the pharmacological treatments, only Riluzole seems to slightly attenuate disease progression extending life span.
ALS is considered as a multi-systemic and multifactorial disease involving different cell types, tissues and molecular mechanisms (1). In particular it has been deeply demonstrated that skeletal muscle plays an important role in ALS pathogenesis according to the "dying back" hypothesis, by which retrograde signals from muscle to nerve can contribute to axon and neuromuscular synapses damage (2).
Several works in literature have demonstrated that ALS patients and animal models of ALS disease (3,4) show, at the presymptomatic phase, a hypermetabolic condition. Recently, we have disclosed this issue revealing that muscle expression of SOD1G93A is associated with metabolic changes and that the alterations in the plasticity and metabolism of muscle fibers occur independently of motor neuron degeneration (5). In line with our observations, previous works (6) demonstrated a metabolic shift of muscle fibers towards a preferential use of lipid oxidative substrate as cellular energy fuel. Therefore the alteration of the metabolic homeostasis represents a crucial event in ALS onset as occurs even before clinical symptoms and motor neuron degeneration.
The present study is the first to provide new insights into the mechanisms that trigger the metabolic alterations in ALS disease, centered into the metabolic circadian control played by hypothalamus and peripherally by skeletal muscle. Indeed, for the first time, we propose to evaluate the relation between circadian induced metabolic alterations and ALS disease with the aim to verify whether the alteration of circadian clock expression can precede ALS clinical symptoms or occur during disease progression. Moreover we propose a novel therapeutic approach, based on a nutritional challenge, to entrain circadian clock, reprogramming it, restoring metabolism and muscle-nerve communication to attenuate ALS disease progression.
Therefore, the achievement of the proposed objectives will have a direct impact on the scientific research in ALS field providing novel interesting insight to combine pharmacological therapy with nutritional complement.
References
1. Musarò A. World J Biol Chem. 2010
2. Dadon-Nachum M, et al J Mol Neurosci. 2011
3. Gorges M, Neurosurg Psychiatry. 2017
4. Vercruysse P. et al., Front Mol Neurosci. 2018
5. Dobrowolny G et al., Front Physiol. 2018
6. Palamiuc L, EMBO Mol Med. 2015