Amyotrophic lateral sclerosis (ALS) is a fatal, multigenic, multifactorial, and non-cell autonomous neurodegenerative disease characterized by upper and lower motor neuron loss. Several genetic mutations lead to ALS development and many emerging gene mutations have been discovered in recent years. Over the decades since 1990, several animal models have been generated to study ALS pathology including both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs, and non-human primates. Although these models show different peculiarities, they are all useful and complementary to dissect the pathological mechanisms at the basis of motor neuron degeneration and ALS progression, thus contributing to the development of new promising therapeutics. In this review, we describe the up to date and available ALS genetic animal models, classified by the different genetic mutations and divided per species, pointing out their features in modeling, the onset and progression of the pathology, as well as their specific pathological hallmarks. Moreover, we highlight similarities, differences, advantages, and limitations, aimed at helping the researcher to select the most appropriate experimental animal model, when designing a preclinical ALS study.

Background and PurposeThe pathogenesis of amyotrophic lateral sclerosis (ALS) is not fully clarified, although excessive glutamate (Glu) transmission and the downstream cytotoxic cascades are major mechanisms for motor neuron death. One and 5 metabotropic Glu (mGlu1,5) receptors are over-expressed in ALS and regulate cellular disease processes. We reported that mGlu5 receptor expression and function are already altered at early symptomatic stages in the SOD1 G93A mouse model of ALS and that knocking-down mGlu5 receptors in SOD1 G93A mice improved the disease scenario. Experimental ApproachWe treated SOD1 G93A mice with 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy) phenyl)-1Himidazol-4-yl)ethynyl)-pyridine (CTEP), an orally available mGlu5 receptor negative allosteric modulator (NAM), at the doses of 2 mg/kg/48h or 4 mg/kg/24h from day 90, an early symptomatic disease stage. Disease progression was studied by behavioural and histological approaches. Key ResultsCTEP, dose dependently ameliorated clinical features in SOD1 G93A mice. The lower dosage increased survival and improved motor skills in female mice, with barely positive effects in male mice. The higher dosage significantly ameliorated disease symptoms and survival in both males and females, being females more responsive. CTEP also reduced motor neurons death, astrocyte and microglia activation and abnormal Glu release in the spinal cord but no differences were observed between male and female mice. No differences were also observed as to the drug access to the brain.

Recent studies reported that the uptake of [18F]-fluorodeoxyglucose (FDG) is increased in the spinal cord (SC) and decreased in the motor cortex (MC) of patients with ALS, suggesting that the disease might differently affect the two nervous districts with different time sequence or with different mechanisms. Here we show that MC and SC astrocytes harvested from newborn B6SJL-Tg (SOD1G93A) 1Gur mice could play different roles in the pathogenesis of the disease. Spectrophotometric and cytofluorimetric analyses showed an increase in redox stress, a decrease in antioxidant capacity and a relative mitochondria respiratory uncoupling in MC SOD1G93A astrocytes. By contrast, SC mutated cells showed a higher endurance against oxidative damage, through the increase in antioxidant defense, and a preserved respiratory function. FDG uptake reproduced the metabolic response observed in ALS patients: SOD1G93A mutation caused a selective enhancement in tracer retention only in mutated SC astrocytes, matching the activity of the reticular pentose phosphate pathway and, thus, of hexose-6P dehydrogenase. Finally, both MC and SC mutated astrocytes were characterized by an impressive ultrastructural enlargement of the endoplasmic reticulum (ER) and impairment in ER–mitochondria networking, more evident in mutated MC than in SC cells. Thus, SOD1G93A mutation differently impaired MC and SC astrocyte biology in a very early stage of life.