Animal models are essential for investigating the pathogenesis and developing the treatment of human diseases. Identification of genetic mutations responsible for neurodegenerative diseases has enabled the creation of a large number of small animal models that mimic genetic defects found in the affected individuals. Of the current animal models, rodents with genetic modifications are the most commonly used animal models and provided important insights into pathogenesis. However, most of genetically modified rodent models lack overt neurodegeneration, imposing challenges and obstacles in utilizing them to rigorously test the therapeutic effects on neurodegeneration. Recent studies that used CRISPR/Cas9-targeted large animal (pigs and monkeys) have uncovered important pathological events that resemble neurodegeneration in the patient's brain but could not be produced in small animal models. Here we highlight the unique nature of large animals to model neurodegenerative diseases as well as the limitations and challenges in establishing large animal models of neurodegenerative diseases, with focus on Huntington disease, Amyotrophic lateral sclerosis, and Parkinson diseases. We also discuss how to use the important pathogenic insights from large animal models to make rodent models more capable of recapitulating important pathological features of neurodegenerative diseases.
Amyotrophic Lateral Sclerosis/genetics* ; Animals ; Brain/pathology* ; Disease Models, Animal ; Gene Editing ; Neurodegenerative Diseases/pathology* ; Swine

OBJECTIVETo perform pathological observation and etiological identification of specimens collected from dairy cows, beef cattle and dogs which were suspected of rabies in Inner Mongolia in 2011, and analyze their etiological characteristics.

METHODSPathological observation was conducted on the brain specimens of three infected animals with Hematoxylin-Eosin staining, followed by confirmation using immunofluorescence and nested RT-PCR methods. Finally, phylogenetic analysis was conducted using the virus N gene sequence amplified from three specimens.

RESULTSEosinophilic and cytoplasmic inclusion bodies were seen in neuronal cells of the CNS; and rabies non-characteristic histopathological changes were also detected in the CNS. The three brain specimens were detected positive. N gene nucleotide sequence of these three isolates showed distinct sequence identity, therefore they fell into different groups in the phylogenetic analysis. N gene in the cow and dog had higher homology with that in Hebei isolate, but that in the beef cattle had higher homology with that in Mongolian lupine isolate and Russian red fox isolate.

CONCLUSIONRabies were observed in the dairy cow, beef cattle and canine in the farm in Inner Mongolia, in 2011, which led to a different etiologic characteristics of the epidemic situation.

Acetazolamide ; Animals ; Brain ; pathology ; Cattle ; Cattle Diseases ; epidemiology ; pathology ; Dog Diseases ; diagnosis ; epidemiology ; Dogs ; Mongolia ; epidemiology ; Nucleoproteins ; genetics ; Phylogeny ; Rabies ; epidemiology ; veterinary ; Rabies virus ; genetics ; Time Factors

OBJECTIVETo analyze the phenotype and genotype of CMTX1 patients with episodic transient reversible white matter involvement, and delineate the features of brain MRI in the episode and the possible mechanisms.

METHODThree Chinese probands and their family members were sequenced in the coding regions of GJB1. With the other 16 reported CMTX1 patients with episodic transient reversible white matter involvement, the clinical feature of the episodic central nervous system symptoms and the genotypes were reviewed.

RESULTMissense mutations in GJB1 were identified in all 3 probands. In 19 patients with transient reversible white matter involvement, the episodes were manifested as weakness of the limbs, dysarthria, and dysphagia, without disturbance of consciousness or seizures. The episodes lasted for 13 hours (10 min-72 hours) with complete remission in all patients; There were multiple episodes in 9 patients. During the episode, brain MRI showed symmetrical high signals in T2 weighted, Flair and DWI images in periventricular white matter, with predominance in posterior region including splenium of corpus callosum. These changes in imaging were most prominent during or within 1 week after the clinical episode.Significant improvements occurred within 1 month, with complete remission within 4-6 months.No specific locations of mutant amino acids in GJB1 protein were found in these patients with episodic transient reversible white matter involvement.

CONCLUSIONEpisodic transient reversible white matter involvement may present in a small number of patients with CMTX1. Transient edema of oligodendrocytes due to the dysfunction of gap junction may be involved in the pathogenesis. There is no correlation between the location of the mutant amino acids in GJB1 and the occurrence of the episodes.

Adolescent ; Brain ; diagnostic imaging ; pathology ; Brain Diseases ; diagnostic imaging ; etiology ; pathology ; Central Nervous System ; pathology ; Charcot-Marie-Tooth Disease ; complications ; genetics ; pathology ; Child ; Connexins ; genetics ; Corpus Callosum ; pathology ; Genetic Linkage ; Humans ; Magnetic Resonance Imaging ; Male ; Mutation, Missense ; Pedigree ; Phenotype ; Radiography

alphaB-crystallin is a member of the sHSP (Small heat shock protein) family, which plays an impor tant role in multiple neurodegeneration diseases. To give insight into the possible alternation and the role of aB-crystallin in prion disease, the alphaB-crystallin levels in the brain tissues of agent 263K-infected hamsters were evaluated. Western blots and IHC revealed that at the terminal stages of the diseases, the levels of alphaB-crystallin were increased up to 3-fold in the brain tissues of scrapie infected 263K hamsters compared with normal controls. Immunofluorescent assays revealed that the up-regulated alphaB-crystallin was mainly observed in astrocytes, but not in neurons. The co-localization between alphaB-crystallin and abnormal deposition of PrPsc in the brain tissues of the scrapie infected hamsters was not observed. The study may provide a foundation for further revealing the potential role of alphaB-crystallin in prion disease.
Animals ; Brain ; metabolism ; pathology ; Cricetinae ; Humans ; PrPSc Proteins ; metabolism ; Prion Diseases ; genetics ; metabolism ; pathology ; Up-Regulation ; alpha-Crystallin B Chain ; genetics ; metabolism

Inflammation is known to participate in the mediation of a growing number of acute and chronic neurological disorders. Even so, the involvement of inflammation in the pathogenesis of epilepsy and seizure-induced brain damage has only recently been appreciated. Inflammatory processes, including activation of microglia and astrocytes and production of proinflammatory cytokines and related molecules, have been described in human epilepsy patients as well as in experimental models of epilepsy. For many decades, a functional role for brain inflammation has been implied by the effective use of anti-inflammatory treatments, such as steroids, in treating intractable pediatric epilepsy of diverse causes. Conversely, common pediatric infectious or autoimmune diseases are often accompanied by seizures during the course of illness. In addition, genetic susceptibility to inflammation correlated with an increased risk of epilepsy. Mounting evidence thus supports the hypothesis that inflammation may contribute to epileptogenesis and cause neuronal injury in epilepsy. We provide an overview of the current knowledge that implicates brain inflammation as a common predisposing factor in epilepsy, particularly childhood epilepsy.
Animals ; Blood-Brain Barrier ; Chronic Disease ; Encephalitis/genetics/immunology/metabolism/*pathology ; Epilepsy/immunology/metabolism/*pathology/therapy ; Gene Expression Regulation ; Humans ; Nervous System Diseases/immunology/pathology

OBJECTIVETo characterize two strains of street rabies virus (RABV) isolated from the brain tissue of cattle from Inner Mongolia. Differences in the histopathological and ultrastructural changes in the brain tissue of infected mice were determined to reveal variation in the pathogenesis of infection between street rabies virus strains.

METHODSTen-day-old mice were intracranially inoculated with one of three virus strains and brain tissue harvested when the mice were moribund. Various histopathological and ultrastructural markers of disease were then compared between the groups.

RESULTSInfection with the street virus strain CNM1101C resulted in severe neuronal dendrites damage, but only mild cell apoptosis, T lymphocyte infiltration and microglial activation. Infection with the other street virus strain, CNM1103C, was characterized by cell apoptosis, T lymphocyte infiltration and microglial activation as well as dendrites damage. However, in comparison, infection with the attenuated virus strain CTN caused severe T lymphocyte infiltration, microglial activation and cell apoptosis, but left the neuronal dendrites intact.

CONCLUSIONThe two street rabies virus strains isolated from cattle from Inner Mongolia had different levels of virulence and caused distinct pathological changes in infected mice. Therefore, we concluded that different pathogenic mechanisms exist between different RABV strains.

Animals ; Brain ; pathology ; virology ; Cattle ; Cattle Diseases ; pathology ; virology ; China ; Fluorescent Antibody Technique, Direct ; Mice ; Mice, Inbred ICR ; Rabies ; pathology ; virology ; Rabies virus ; genetics ; pathogenicity ; physiology ; ultrastructure ; Virulence

OBJECTIVETo investigate whether gliosis in the brain tissues of the hamsters infected with various amounts of scrapie strain 263K is correlated with the inoculation doses or the incubation times.

METHODSThe total values of glial fibrillary acidic protein (GFAP) in brains were evaluated by Western Blots and the GFAP-stained cells were detected by immunohistochemistry (IHC). The characteristics of GFAP distributions among various groups were defined by quantitive and statistic analyses.

RESULTSCompared with the brain tissues of normal hamsters, remarkably higher total GFAP levels and more GFAP-stained cells were observed in the brain tissues of infected ones, howbeit, no significant difference was addressed among the infected groups.

CONCLUSIONInoculations of various amounts of scrapie strain 263K into experimental hamsters intracerebrally induced the similar patterns of gliosis in the brains at the clinically terminal stage, regardless of infectious doses and incubation times.

Animals ; Brain ; metabolism ; pathology ; Cricetinae ; Gene Expression ; Glial Fibrillary Acidic Protein ; genetics ; metabolism ; Gliosis ; metabolism ; pathology ; Humans ; PrPSc Proteins ; metabolism ; Prion Diseases ; metabolism ; pathology

This study reviews a case of mitochondrial respiratory chain complex I deficiency due to the 10191T>C mutation in mitochondrial ND3 gene. The previously healthy boy progressively presented with blepharoptosis, weakness, epilepsy and motor regression at age 6 years. Elevated blood lactate and pyruvate were observed. Brain magnetic resonance imaging showed symmetrical lesions in the basal ganglia. Leigh syndrome was thus confirmed. The protein from the mitochondria and genomic DNA of the boy and his parents was collected from peripheral blood leucocytes for the activity test for mitochondrial complex I to V and genetic analysis. The results showed the activity of complex I (33.1 nmol /min in 1 milligram mitochondrial protein) was lower than normal reference value (44.0±5.4 nmol /min in 1 milligram mitochondrial protein). The ratio of complex I to citrate synthase (19.8%) was also lower than normal reference value (48%±11%). The activities of complexes II to V were normal. 10191T>C mutation in ND3 gene of mitochondria was identified in the boy. 10191T>C mutation and complex I deficiency were not detected in his parents. At present, he is 16 years old, and of normal intelligence with spastic paralysis in both lower extremities after treatment. It is concluded that a Chinese boy with isolated complex I deficiency due to 10191T>C mutation in ND3 gene was firstly diagnosed by peripheral leukocytes mitochondrial respiratory chain enzyme assay and gene analysis. This study can provide clinical data for the nosogenesis of Leigh syndrome.
Adolescent ; Brain ; pathology ; Electron Transport Complex I ; deficiency ; genetics ; Humans ; Leigh Disease ; genetics ; Magnetic Resonance Imaging ; Male ; Mitochondrial Diseases ; genetics ; Mutation

OBJECTIVEThe authors sought to investigate the clinical features and characteristics of genetic mutation in patients with aspartylglucosaminuria.

METHODClinical data of two pediatric siblings in a family were analyzed retrospectively and relative literature was reviewed in order to study the clinical features, imaging and enzymatic characteristics and genetic mutations.

RESULTCase 1, the proband, male, he was hospitalized at 20 months of age because of fever and hepatosplenomegaly for nine days. This child was of moderate nutritional status and normal development. Blood tests showed hemoglobin 78.0 g/L, RBC3.18 × 10¹²/L, WBC 4.06 × 10⁹/L, neutrophils 0.236, lymphocytes 0.631, platelets 34 × 10⁹/L, C-reactive protein 17 mg/L. Blood biochemistry showed alanine aminotransferase 67.1 U/L, aspartate aminotransferase 74.1 U/L, serum albumin 32.8 g/L, direct bilirubin 10.5 µmol/L, lactate dehydrogenase 301.7 U/L. Bone marrow cytology showed reactive morphological changes in bone marrow cells. Atypical lymphocytes could be seen in both peripheral blood and bone marrow smears. Cranial MRI showed poor myelination. Aspartylglucosaminidase activity in peripheral leucocytes of the proband 5.7 nmol/(g × min) vs. normal control>26.6 nmol/(g × min). On his AGA gene and that of his parents, a heterozygous mutation site located in exon 3, c.392C>T (p.S131L), was identified as a novel mutation inherited from his father. The mutation from his mother has not been detected. The proband was not responsive to the anti-infectious medication, nutritional intervention and symptomatic treatment.He died one month after diagnosis.His elder brother, Case 2, showed fever, recurrent respiratory tract infection and progressive psychomotor regression with hepatosplenomegaly from the age of four years. Cranial MRI revealed extensive symmetrical leukodystrophy in bilateral cerebra, cerebellum and brainstem.He died at the age of six years.Related literature was summarized, and no Chinese AGU cases had been reported; 221 foreign cases were collected. The clinical and imaging characteristics were summarized. Delay in language development was one of the clinical symptoms that the majority of parents of AGU children first noted.

CONCLUSIONPatients with aspartylglucosaminuria lack of specific symptoms.For children with unexplained delayed speech and progressive mental retardation, the possibility of AGU should be considered, and efforts be made for enzymatic and genetic diagnosis. c.392C> T (p.S131L) was identified as a novel mutation of AGA gene.

Aspartylglucosaminuria ; diagnosis ; genetics ; pathology ; Aspartylglucosylaminase ; genetics ; metabolism ; Biomarkers ; blood ; Brain ; pathology ; Child, Preschool ; DNA Mutational Analysis ; Heterozygote ; Humans ; Infant ; Lysosomal Storage Diseases ; diagnosis ; genetics ; pathology ; Magnetic Resonance Imaging ; Male ; Mutation ; Pedigree ; Polymerase Chain Reaction

The neuronal migration disorders, X-linked lissencephaly syndrome (XLIS) and subcortical band heterotopia (SBH), also called "double cortex", have been linked to missense, nonsense, aberrant splicing, deletion, and insertion mutations in doublecortin (DCX) in families and sporadic cases. Most DCX mutations identified to date are located in two evolutionarily conserved domains. We performed mutation analysis of DCX in two Korean patients with SBH. The SBH patients had mild to moderate developmental delays, drug-resistant generalized seizures, and diffuse thick SBH upon brain MRI. Sequence analysis of the DCX coding region in Patient 1 revealed a c.386 C>T change in exon 3. The sequence variation results in a serine to leucine amino acid change at position 129 (S129L), which has not been found in other family members of Patient 1 or in a large panel of 120 control X-chromosomes. We report here a novel c.386 C>T mutation of DCX that is responsible for SBH.
Adolescent ; Adult ; Base Sequence ; Brain Diseases/*genetics/pathology ; *Cerebral Cortex ; Choristoma/*genetics/pathology ; DNA Mutational Analysis ; Female ; Humans ; Magnetic Resonance Imaging ; Microtubule-Associated Proteins/*genetics ; *Mutation, Missense ; Neuropeptides/*genetics ; Research Support, Non-U.S. Gov't