Hind Limb Weakness Research Articles

Autoimmune polyendocrine syndrome in a standard poodle with concurrent non‐endocrine immune‐mediated diseases

AbstractA 6‐year‐old female neutered standard poodle was referred with a 4‐week history of rapidly progressive weight loss, muscle atrophy, hyporexia, hind limb weakness and lethargy. In the preceding 3‐month period, the dog had been diagnosed with both keratoconjunctivitis sicca (KCS) and hypoadrenocorticism. Clinical deterioration had occurred despite treatment for hypoadrenocorticism. Following referral, the dog was diagnosed with concurrent hypothyroidism, exocrine pancreatic insufficiency (EPI) and suspected generalised myositis. Treatment with hormone replacement therapy, pancreatic enzyme supplementation and immunosuppressive doses of prednisolone and mycophenolate resulted in marked clinical improvement. This case describes a rapidly progressive, presumed autoimmune, polyglandular endocrinopathy in a dog with concurrent non‐endocrine autoimmune diseases.

A Physiological-Based Pharmacokinetic Model For The Broad Spectrum Antimicrobial Zinc Pyrithione: II. Dermal Absorption And Dosimetry In The Rat

ABSTRACT The broad spectrum antimicrobial/antifungal zinc pyrithione (ZnPT) is used in products ranging from antifouling paint to antidandruff shampoo. The hazard profile of ZnPT was established based upon comprehensive toxicological testing, and products containing this biocide have been safely used for years. The purpose of this study was to create a dermal physiologically based pharmacokinetic (PBPK) model for ZnPT in the rat for improving dose–response analysis of ZnPT-induced toxicity where reversible hindlimb weakness was the endpoint used as the basis for ZnPT risk assessments. Previously, we developed a PBPK model which simulated the kinetics of pyrithione (PT) and its major metabolites 2-(methylsulfonyl)pyridine and S-glucuronide conjugates in blood and tissues of rats following oral ZnPT administration. The dermal model was optimized utilizing in vitro dermal penetration investigations conducted with rat skin and with historical data from a dermal repeat dose study using rats. The model replicated the observed temporal patterns and elimination kinetics of [14C]PT equivalents in blood and urine during and following repeated dermal dosing and replicated the observed dose-dependencies of absorption, blood [14C]PT equivalents and plasma PT concentrations. The model provided internal dosimetry predictions for a benchmark dose analysis of hindlimb weakness in rats that combined dermal, gavage and dietary studies into a single internal dose–response model with area-under-the-curve (AUC) for plasma PT, the toxic moiety in the rat, as the internal dose metric. This PBPK model has predictive validity for calculating internal doses of PT and/or [14C]PT equivalents from different routes of exposure in the rat.

Spontaneous chordoma: a case report on a female UM-HET3 mouse from the SLAM study.

A female UM-HET3 mouse from the Study of Longitudinal Aging in Mice (SLAM) was euthanized at 164 weeks of age due to hind limb weakness. Necropsy and histological analysis revealed that the most probable cause of the clinical finding was the compression of the thoracolumbar segment of the spinal cord by herniated intervertebral disks. In addition, a spontaneous chordoma was incidentally found in the coccygeal bones. Given the rarity of this type of tumor, bio-clinical annotations acquired throughout lifespan, detailed histopathological assessment, and comparative clinical-pathological correlations for this mouse are presented and discussed.

A clinical study of equine trypanosomosis in Kerala

This study was done on three female Marwari horses 3, 4 and 5 years old from Pookkottur, Areekode and Mankada (Case no. 1, 2 and 3 respectively) in Malappuram district of Kerala. The mares showed inappetance, lethargy, weight loss, scanty and watery faeces, yellowish discoloration of urine and hind limb weakness. Physical examination was carried out and blood samples were collected for laboratory investigation. Clinical examination revealed, all the animals were debilitated with pale and moist mucous membrane, pyrexia, prolonged capillary refill time, tachypnoea and tachycardia. Laboratory investigation revealed the presence of Trypanosoma sp. in all the three cases. Haematological examination revealed low Haemoglobin, Packed Cell Volume and Total Erythrocyte Count. The treatment was done using Diminazine aceturate (7 mg/kg bodyweight, intramuscular), two doses in 7 days interval. A screening done after a week revealed all mares were free from parasite. All mares had an uneventful recovery.

Protocatechuic Acid Extends Survival, Improves Motor Function, Diminishes Gliosis, and Sustains Neuromuscular Junctions in the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by motor neuron apoptosis and subsequent skeletal muscle atrophy caused by oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation. Anthocyanins are polyphenolic compounds found in berries that possess neuroprotective and anti-inflammatory properties. Protocatechuic acid (PCA) is a phenolic acid metabolite of the parent anthocyanin, kuromanin, found in blackberries and bilberries. We explored the therapeutic effects of PCA in a transgenic mouse model of ALS that expresses mutant human Cu, Zn-superoxide dismutase 1 with a glycine to alanine substitution at position 93. These mice display skeletal muscle atrophy, hindlimb weakness, and weight loss. Disease onset occurs at approximately 90 days old and end stage is reached at approximately 120 days old. Daily treatment with PCA (100 mg/kg) by oral gavage beginning at disease onset significantly extended survival (121 days old in untreated vs. 133 days old in PCA-treated) and preserved skeletal muscle strength and endurance as assessed by grip strength testing and rotarod performance. Furthermore, PCA reduced astrogliosis and microgliosis in spinal cord, protected spinal motor neurons from apoptosis, and maintained neuromuscular junction integrity in transgenic mice. PCA lengthens survival, lessens the severity of pathological symptoms, and slows disease progression in this mouse model of ALS. Given its significant preclinical therapeutic effects, PCA should be further investigated as a treatment option for patients with ALS.

An overview of dropped hock syndrome cases in New Zealand cattle

ABSTRACTCase history: Data were collected from 47 outbreaks of dropped hock syndrome (DHS) that were reported by veterinarians in New Zealand to the Ministry for Primary Industries between October 2012 and August 2017. There were 181 affected dairy cows from 44 farms. Of those with records, all 86 were aged between 2–3 years-old, and 4/94 (4%) were Friesian, 56/94 (60%) were Jersey and 33/94 (35%) were Jersey/Friesian cross. Of the 47 outbreaks, 45 (96%) occurred during winter and 37 (79%) in the South Island.Clinical findings: Of 151 cases with records, hindlimb weakness (117 cows), shortened gait (112 cows) and dropped hocks (106 cows) were most commonly reported, with 110 cases being bilaterally affected. The level of diagnostic work-up and the data recorded by veterinarians for each outbreak were highly variable. Creatine kinase and aspartate aminotransferase activities were reported for 22 cases and were within normal ranges for cows with mild disease but increased in cows with severe disease. Concentrations of Cu in serum and liver were below normal for 13/22 and 9/10 cows, respectively, from six outbreaks. Of 41 cows with records for clinical outcomes, 12 had complete resolution, 18 had partial resolution, and 11 had no resolution.Pathological findings: Post-mortem data were available from 26 cases. Muscle necrosis and haemorrhage of the origin of the gastrocnemius muscle were the key gross findings. In 14 cows with records for muscle histopathology, myodegeneration and recent haemorrhage were observed, and connective tissue pathology was reported to predate muscular pathology in seven cases.Diagnosis: DHS appeared to be a degenerative rather than inflammatory condition primarily affecting the connective tissue of the hind limb, especially at the dense collagen interfaces of the gastrocnemius. Although no evidence of neuropathy was found, this cannot definitively be ruled out as a potential cause.Clinical relevance: A more standardised and systematic approach to investigating cases and recording case data is required to make robust inferences about the aetiology, risk factors, and treatment interventions for DHS.

Mycobacteriosis in a Zoo Population of Chinese Gliding Frogs (Rhacophorus dennysi) Due to Mycobacterium marinum

Mycobacteriosis was implicated in the deaths of eight Chinese gliding frogs (Rhacophorus dennysi) in a zoo population over a 3 yr period. Clinical signs included nonhealing skin lesions, cloacal prolapse, hind limb weakness, weight loss, and sudden death. Abnormalities on postmortem were proliferative or ulcerative skin lesions in four of eight, pneumonia in three of eight, and gall bladder empyema in two of eight cases. All eight clinical cases had multisystemic granulomas containing acid-fast bacilli. Tissues most commonly affected were lung (seven of eight), liver (six of eight), kidney (six of eight), spleen (five of eight), and heart (five of eight). The remaining eight clinically normal frogs in the population were euthanized: eight of eight had granulomatous lesions, with acid-fast bacilli in three of eight cases. A mycobacterial species was cultured from four of the clinical cases by the Public Health Ontario Laboratory and was initially misidentified as Mycobacterium tuberculosis complex by a commercial line-probe assay (GenoType Mycobacterium CM, Hain Lifesciences, Nehren, Germany). Further diagnostic testing using 16S rRNA gene sequencing ultimately identified the mycobacterial species as Mycobacterium marinum. The correct identification of mycobacterial species is essential in epidemiological investigations at zoological facilities, and in assessing health risks to staff and to other animals in the zoo population.

West Nile Virus Infection in Human and Animals: Potential Risks in Malaysia

West Nile virus (WNV) is a zoonotic RNA virus maintained in enzootic cycles involving mosquito mainly Culex and Aedes spp. as the vector and birds as the reservoir host. WNV is endemic in Africa, Europe and Western Asia. Human infection results in asymptomatic illness such as fever, headache, tiredness, body aches, nausea, vomiting, skin rash, swollen lymph glands and neuroinvasive disease are seen in less than 1% of infected persons. The spectrum of symptoms in animals includes fever, weakness and paralysis of hind limbs, impaired vision, ataxia, head pressing, aimless wandering, seizures, inability to swallow, walking in circles and coma. Based on the previous study in Malaysia, the antibody and nucleic acid against WNV were detected in Orang Asli, captive birds and horses. In this paper, potential risk factors contributing to WNV occurrence are discussed. How the disease or infection is diagnosed and controlled was also discussed.

Diagnosis and Treatment of a Cervical Vertebral Fracture in a Sulcata Tortoise (Centrochelys sulcata)

A 17-yr-old, 22.2-kg, intact female sulcata tortoise (Centrochelys sulcata) was presented for evaluation of a suspected intestinal obstruction and a 2-month history of hind-limb weakness, anorexia, lack of defecation, and decreased urine production. Clinical signs included generalized subcutaneous edema, pelvic limb paresis, decreased vent tone, and ataxia. Computed tomography (CT) identified findings consistent with a chronic compression fracture of the eighth cervical vertebrae with severe extradural compression of the spinal cord and near-complete obliteration of the vertebral canal. The tortoise was medically managed in the hospital for 13 days and discharged with analgesic and antibiotic medications. Over the following weeks, the tortoise regained an ability to defecate and urinate, and the tortoise's motor deficits mildly improved. A recheck contrast CT at 39 wk postdischarge was consistent with remodeling of the chronic compression fracture and mildly improved extradural compression of the spinal cord. Approximately 2 yr after the initial presentation, the motor limb deficits were still present. Thirty-three months after initial presentation, the tortoise presented obtunded and with anasarca. The tortoise was euthanized, and the necropsy revealed bilateral demyelination with moderate axonal loss, astrocyte reactivity, and moderate dural fibrosis in the spinal cord, consistent with chronic compression at the level of C8. This report illustrates an unusual presentation of a chronic cervical vertebral fracture and spinal cord compression that was diagnosed and monitored via CT, the treatment and recovery of most of the initial clinical signs and persistent motor limb deficits, as well as the postmortem spinal cord histologic findings.

Bilateral lateral patellar luxation in a calf

This case report documents the surgical treatment of bilateral lateral patellar luxation in a calf and the outcome by clinical examination, radiography, CT and postmortem examination. A 21-day-old calf was...

An adult gerbil model for evaluating potential coxsackievirus A16 vaccine candidates

A suitable animal model of CVA16 infection is crucial in order to understand its pathogenesis and to help develop antiviral vaccines or screen therapeutic drugs. The neonatal mouse model has a short sensitivity period to CA16 infection, which is a major limitation. In this study, we demonstrate that adult (60-day-old) gerbils are susceptible to CVA16 infection at high doses (108.0 TCID50). A clinical isolate strain of CVA16 was inoculated intraperitoneally into adult gerbils, which subsequently developed significant clinical symptoms, including hind limb weakness, paralysis of one or both hind limbs, tremors, and eventual death from neurological disorders. Real-time RT-PCR revealed that viral loads in the spinal cord and brainstem were higher than those in other organs/tissues. Histopathological changes, such as neuronal degeneration, neuronal loss, and neuronophagia, were observed in the spinal cord, brainstem, and heart muscle, along with necrotizing myositis. Gerbils receiving both prime and boost immunizations of alum adjuvant inactivated vaccine exhibited no clinical signs of disease or mortality following challenge by CVA16, whereas 80% of control animals showed obvious clinical signs, including slowness, paralysis of one or both hind limbs, and eventual death, suggesting that the CVA16 vaccine can fully protect gerbils against CVA16 challenge. These results demonstrate that an adult gerbil model provides us with a useful tool for studying the pathogenesis and evaluating antiviral reagents of CVA16 infection. The development of this animal model would also be conducive to screening promising CVA16 vaccine candidates as well as further vaccination evaluation.

Cervical diskospondylitis in a Tennessee walking horse mare

A 17-year-old Tennessee Walking Horse mare presented for an approximate four-week history of hindlimb weakness and suspect laminitis, as perceived by the owner. When examined by a veterinarian, no lameness...

Rab18 Collaborates with Rab7 to Modulate Lysosomal and Autophagy Activities in the Nervous System: an Overlapping Mechanism for Warburg Micro Syndrome and Charcot-Marie-Tooth Neuropathy Type 2B.

Mutations in RAB18, a member of small G protein, cause Warburg micro syndrome (WARBM), whose clinical features include vision impairment, postnatal microcephaly, and lower limb spasticity. Previously, our Rab18-/- mice exhibited hind limb weakness and spasticity as well as signs of axonal degeneration in the spinal cord and lumbar spinal nerves. However, the cellular and molecular function of RAB18 and its roles in the pathogenesis of WARBM are still not fully understood. Using immunofluorescence staining and expression of Rab18 and organelle markers, we find that Rab18 associates with lysosomes and actively traffics along neurites in cultured neurons. Interestingly, Rab18-/- neurons exhibit impaired lysosomal transport. Using autophagosome marker LC3-II, we show that Rab18 dysfunction leads to aberrant autophagy activities in neurons. Electron microscopy further reveals accumulation of lipofuscin-like granules in the dorsal root ganglion of Rab18-/- mice. Surprisingly, Rab18 colocalizes, cofractionates, and coprecipitates with the lysosomal regulator Rab7, mutations of which cause Charcot-Marie-Tooth (CMT) neuropathy type 2B. Moreover, Rab7 is upregulated in Rab18-deficient neurons, suggesting a compensatory effect. Together, our results suggest that the functions of RAB18 and RAB7 in lysosomal and autophagic activities may constitute an overlapping mechanism underlying WARBM and CMT pathogenesis in the nervous system.

Diabetes mellitus en hypercortisolisme bij een kat

Een veertien jaar oude Perzische kat werd doorverwezen vanwege slecht gereguleerde diabetes mellitus ondanks insulinebehandeling en een aangepast dieet. De kat vertoonde uitgesproken polyurie/polydipsie, een slechte vachtkwaliteit, stomatitis en zwakte op de achterhand. Op dat moment werd hij behandeld met glargine insuline (0,75 IE/kg BID). Met behulp van een lage-dosis-dexamethasone-suppressie-test (LDDST) werd hypercortisolisme (HC) gediagnostiseerd. De kat werd bijkomend behandeld met trilostane en één jaar later werd remissie van diabetes mellitus bekomen. Deze casuïstiek illustreert het belang van de diagnose van een onderliggende oorzaak van slecht gereguleerde diabetes mellitus. Ook al is hypercortisolisme zeldzaam bij katten, het is belangrijk de ziekte bij deze gevallen in de differentiaaldiagnose op te nemen. Hypercortisolisme werd bij deze patiënt behandeld met trilostane, resulterend in een goede levenskwaliteit.

Primary central nervous system neoplasms in African hedgehogs.

In this retrospective study, we describe the clinicopathologic and immunohistochemical findings in a series of primary central nervous system (CNS) neoplasms in African hedgehogs ( Atelerix albiventris). Twelve CNS neoplasms were found among 762 African hedgehog submissions (1.6%) to a private diagnostic laboratory in an 18-y period. The median age of affected hedgehogs was 3.5 y. No sex predilection was found. Hindlimb paresis, weakness, and ataxia were the most commonly reported clinical signs. Gangliogliomas ( n = 6) and astrocytomas ( n = 5) were the most commonly observed neoplasms; one oligodendroglioma was found. Gangliogliomas were found in the cerebellar white matter (2 of 6), brainstem (4 of 6), cervical spinal cord (1 of 6), and frontal lobe (1 of 6); one metastasized to the tongue. Gangliogliomas were immunoreactive for neurofilament protein (NFP), glial fibrillary acidic protein (GFAP), S100, and CD34. All astrocytomas were gemistocytic, located in the cerebrum, and none of these neoplasms metastasized. Astrocytomas were positive for GFAP, S100, and CD34, but negative for NFP. The oligodendroglioma was located in the cerebrum, and was positive for S100, but negative for GFAP and NFP.

Neurologic Complications Associated with Transdermal Placement of Intrathecal Catheters in Sheep.

A study using an ovine model of transdermal intrathecal catheterization was planned to investigate the neurotoxicity of magnesium sulfate. Nonpregnant Merino cross ewes (n = 8; age, 5 y; weight, 55.0 ± 6.5 kg) were anesthetized for placement of a lumbar intrathecal catheter. The study protocol defined a 5-d recovery period after introduction of the catheter before the administration of test substances (2 mL of 0.9% saline or 50 or 150 mg MgSO4) followed by euthanasia 1 wk later. Although 3 sheep successfully completed the study as planned, one of the remaining 5 sheep was withdrawn when the catheter was accidentally dislodged 2 d after anesthesia; another was withdrawn because of persistent neurologic deficits of the left hindlimb and intense pruritus during the first 24 h after placement of the catheter; and the remaining 3 animals experienced unacceptable complications within the first 4 h of administration of the test substance. These complications included hindlimb weakness, intense irritation or pruritus of the hindlimbs, recumbency, inability to stand, spasm of the hindlimb, and arching of the back. Postmortem examination of 4 sheep with clinical signs revealed similar gross findings: acute, segmental myelomalacia and hemorrhage within the spinal cord parenchyma in the region of the catheter. Histologic changes included segmental areas of acute myelomalacia, consistent with the intraparenchymal placement of the catheter. Postmortem CT imaging of 3 sheep confirmed the location of the catheter within the spinal cord. Procedural refinement for the placement of intrathecal catheters in sheep by avoiding an invasive surgical procedure was unsuccessful. We therefore recommend a complete or partial surgical approach for the insertion of an intrathecal catheter in sheep or fluoroscopy or ultrasonography intraoperatively to confirm correct placement of the catheter.

Fingolimod therapy is not effective in a mouse model of spontaneous autoimmune peripheral polyneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disorder, which causes progressive sensory and motor deficits and often results in severe disability. Knockout of the co-stimulatory protein CD86 in mice of the non-obese diabetic background (NoD.129S4-Cd86tm1Shr/JbsJ) results in the development of a spontaneous autoimmune peripheral polyneuropathy (SAPP). We used this previously described transgenic model to study the effects of the sphingosine-1-phosphate receptor agonist fingolimod on SAPP symptoms, functional and electrophysiological characteristics. Compared to two control strains, knockout of CD86 in NOD mice (CD86−/− NOD) resulted in progressive paralysis with distinct locomotor deficits due to a severe sensory-motor axonal-demyelinating polyneuropathy as assessed by electrophysiological measurements. We started fingolimod treatment when CD86−/− NOD mice showed signs of unilateral hind limb weakness and continued at a dose of 1 mg/kg/day for eight weeks. We did not observe any beneficial effects of fingolimod regarding disease progression. In addition, fingolimod did not influence the functional outcome of CD86−/− NOD mice compared to vehicle treatment nor any of the electrophysiological characteristics. In summary, we show that fingolimod treatment has no beneficial effects in autoimmune polyneuropathy, which is in line with recent clinical data obtained in CIDP patients.

Multifocal discrete osteolysis in a horse with silicate associated osteoporosis.

Silicate associated osteoporosis (SAO) was diagnosed post mortem in an adult horse with the shortest documented exposure to cytotoxic silicates of 2 years. The horse was evaluated for a 6-months history of progressive back tenderness and acute onset of lameness. The horse had a marked (4/5) [American Association of Equine Practitioners scale] left forelimb lameness, moderate (2/5) hindlimb ataxia and weakness, and cervical pain upon palpation. Physical examination did not reveal clinical skeletal deformities or respiratory compromise. Radiographs revealed widespread, discrete, sharply delineated, osteolytic lesions in the skull, vertebral column, ribs, scapulae and middle phalanx (P2) of the left forelimb and a diffuse bronchointerstitial lung pattern. The presumptive clinical diagnosis was widespread, metastatic osteolytic neoplasia. Due to the poor quality of life and grave prognosis, the horse was humanely euthanised. Post mortem examination revealed pulmonary silicosis in the lungs and hilar lymph nodes and osteolytic lesions with numerous, large osteoclasts and disorganised bone remodeling both consistent with SAO. SAO should be included as a differential diagnosis for horses with widespread, multifocal, discrete osteolysis and history of exposure to endemic regions with possible cytotoxic silicate inhalation. Exposure time of 2 years is potentially sufficient to develop SAO.

Pharmacological inhibition of the NLRP3 inflammasome as a potential target for multiple sclerosis induced central neuropathic pain.

The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is implicated in the pathogenesis of multiple diseases including neuroinflammation associated with multiple sclerosis (MS). However, the extent to which NLRP3 has a pathobiological role in MS-associated central neuropathic pain (CNP) is unknown. Hence, the present study was designed to address this issue using an optimised relapsing-remitting experimental encephalomyelitis (RR-EAE)-mouse model of MS-associated neuropathic pain. RR-EAE mice with fully developed mechanical allodynia in the bilateral hindpaws (paw withdrawal thresholds (PWTs)≤1g) at day 16 post-immunisation (p.i.) were administered single oral bolus doses of MCC950, a selective and potent small-molecule inhibitor of NLRP3, once daily for 21 consecutive days. Following administration of the first dose of MCC950 at 50 mgkg-1, the mean (±SEM) peak anti-allodynic effect was observed at~1h post-dosing with a duration of action of~2h. Following chronic dosing with MCC950, mechanical allodynia in the bilateral hindpaws was progressively reversed by oral treatment with MCC950 (50 mgkg-1day-1), but not vehicle. Specifically, by day 25 p.i. and continuing until study completion on day 36 p.i., bilateral hindpaw PWTs of RR-EAE mice treated with MCC950 (50 mgkg-1day-1) did not differ significantly (P>0.05) from the corresponding hindpaw PWTs for the sham (control) group. In addition, MCC950 at 50 mgkg-1day-1 attenuated disease relapses in RR-EAE mice indicated by tail limpness as well as hindlimb weakness. Together, our findings suggest that inhibition of NLRP3 inflammasome activation may be a potential therapeutic approach to alleviate MS-associated CNP and disease relapses in patients with RR-MS.

Mutation of the caspase-3 cleavage site in the astroglial glutamate transporter EAAT2 delays disease progression and extends lifespan in the SOD1-G93A mouse model of ALS

Downregulation in the astroglial glutamate transporter EAAT2 in amyotrophic lateral sclerosis (ALS) patients and mutant SOD1 mouse models of ALS is believed to contribute to the death of motor neurons by excitotoxicity. We previously reported that caspase-3 cleaves EAAT2 at a unique cleavage consensus site located in its c-terminus domain, a proteolytic cleavage that also occurs in vivo in the mutant SOD1 mouse model of ALS and leads to accumulation of a sumoylated EAAT2 C-terminus fragment (CTE-SUMO1) beginning around onset of disease. CTE-SUMO1 accumulates in PML nuclear bodies of astrocytes and causes them to alter their mature phenotypes and secrete factors toxic to motor neurons.Here, we report that mutating the caspase-3 consensus site in the EAAT2 sequence with an aspartate to asparagine mutation (D504N), thereby inhibiting caspase-3 cleavage of EAAT2, confers protection to the SOD1-G93A mouse. EAAT2-D504N knock-in mutant mice were generated and crossed with SOD1-G93A mice to assess the in vivo pathogenic relevance for ALS symptoms of EAAT2 cleavage. The mutation did not affect normal EAAT2 function nor non-ALS mice. In agreement with the timing of CTE-SUMO1 accumulation, while onset of disease was not affected, the mutation caused an extension in progression time, a delay in the development of hindlimb and forelimb muscle weakness, and a significant increase in the lifespan of SOD1-G93A mice.