R.unige.it (T.B.); [email protected] (R.A.
R.unige.it (T.B.); [email protected] (R.A.Z.); [email protected] (M.B.); [email protected] (C.T.); [email protected] (G.F.); [email protected] (G.B.); [email protected] (M.M.) Inter-University Center for the Promotion of your 3Rs Principles in Teaching Analysis (Centro 3R), 56122 Genoa, Italy IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy Polmacoxib cox Correspondence: [email protected]: Bonifacino, T.; Zerbo, R.A.; Balbi, M.; Torazza, C.; Frumento, G.; Fedele, E.; Bonanno, G.; Milanese, M. Almost 30 Years of Animal Models to Study Amyotrophic Lateral Sclerosis: A Historical Overview and Future Perspectives. Int. J. Mol. Sci. 2021, 22, 12236. https://doi.org/10.3390/ ijms222212236 Academic Editor: Changjong Moon Received: 24 September 2021 Accepted: 9 November 2021 Published: 12 NovemberAbstract: Amyotrophic lateral sclerosis (ALS) can be a fatal, multigenic, multifactorial, and non-cell autonomous neurodegenerative disease characterized by upper and reduced motor neuron loss. Numerous genetic mutations bring about ALS improvement and lots of emerging gene mutations have already been discovered in current years. Over the decades since 1990, quite a few animal models have already been generated to study ALS pathology including each vertebrates and invertebrates for instance yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs, and non-human primates. Although these models show various peculiarities, they may be all valuable and complementary to dissect the pathological mechanisms in the basis of motor neuron degeneration and ALS progression, therefore contributing for the development of new promising therapeutics. Within this critique, we describe the up to date and readily available ALS genetic animal models, classified by the MRTX-1719 manufacturer diverse genetic mutations and divided per species, pointing out their characteristics in modeling, the onset and progression of the pathology, at the same time as their precise pathological hallmarks. In addition, we highlight similarities, differences, advantages, and limitations, aimed at helping the researcher to pick probably the most suitable experimental animal model, when designing a preclinical ALS study. Keywords and phrases: amyotrophic lateral sclerosis; genetic animal models; yeast; worm; fly; zebrafish; mouse; rat; guinea pig; dog; swine; non-human primatesPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.1. Introduction Amyotrophic lateral sclerosis (ALS), also referred to as Charcot’s or Lou Gehrig’s illness, is usually a multisystem neurodegenerative disease, characterized by heterogeneity at the genetic, neuropathological, and clinical levels [1]. The progressive degeneration of upper and reduced motoneurons (MNs) happens for the duration of disease progression and impacts pyramidal cells inside the cortex, the corticospinal tract, and spinal motoneurons, generally sparing the extraocular and sphincter muscle tissues [1]. The effects of MN loss evolve in muscle weakness, fasciculations, atrophy, spasticity, and hyperreflexia, at some point top to paralysis, and sufferers typically die due to respiratory failure within three to 5 years from diagnosis [4,5]. Early pathogenic processes involve axonal degeneration and impairment of nerve terminal function, anticipating MN loss, along with the onset of clinical symptoms [6]. Quite a few causes happen to be proposed because the basis with the disease onset and progression, such as excessive calcium and glutamate excitotoxicity [74], oxidative stress [157], axonal damage and transport dy.