Zebrafish and Medaka: Important Animal Models for Human Neurodegenerative Diseases

Animal models of human neurodegenerative disease have been investigated for several decades. In recent years, zebrafish (Danio rerio) and medaka (Oryzias latipes) have become popular in pathogenic and therapeutic studies about human neurodegenerative diseases due to their small size, the optical clarity of embryos, their fast development, and their suitability to large-scale therapeutic screening. Following the emergence of a new generation of molecular biological technologies such as reverse and forward genetics, morpholino, transgenesis, and gene knockout, many human neurodegenerative disease models, such as Parkinson’s, Huntington’s, and Alzheimer’s, were constructed in zebrafish and medaka. These studies proved that zebrafish and medaka genes are functionally conserved in relation to their human homologues, so they exhibit similar neurodegenerative phenotypes to human beings. Therefore, fish are a suitable model for the investigation of pathologic mechanisms of neurodegenerative diseases and for the large-scale screening of drugs for potential therapy. In this review, we summarize the studies in modelling human neurodegenerative diseases in zebrafish and medaka in recent years.

BMAA, Methylmercury, and Mechanisms of Neurodegeneration in Dolphins: A Natural Model of Toxin Exposure

Dolphins are well-regarded sentinels for toxin exposure and can bioaccumulate a cyanotoxin called β-N-methylamino-l-alanine (BMAA) that has been linked to human neurodegenerative disease. The same dolphins also possessed hallmarks of Alzheimer’s disease (AD), suggesting a possible association between toxin exposure and neuropathology. However, the mechanisms of neurodegeneration in dolphins and the impact cyanotoxins have on these processes are unknown. Here, we evaluate BMAA exposure by investigating transcription signatures using PCR for dolphin genes homologous to those implicated in AD and related dementias: APP, PSEN1, PSEN2, MAPT, GRN, TARDBP, and C9orf72. Immunohistochemistry and Sevier Münger silver staining were used to validate neuropathology. Methylmercury (MeHg), a synergistic neurotoxicant with BMAA, was also measured using PT-GC-AFS. We report that dolphins have up to a three-fold increase in gene transcription related to Aβ+ plaques, neurofibrillary tangles, neuritic plaques, and TDP-43+ intracytoplasmic inclusions. The upregulation of gene transcription in our dolphin cohort paralleled increasing BMAA concentration. In addition, dolphins with BMAA exposures equivalent to those reported in AD patients displayed up to a 14-fold increase in AD-type neuropathology. MeHg was detected (0.16–0.41 μg/g) and toxicity associated with exposure was also observed in the brain. These results demonstrate that dolphins develop neuropathology associated with AD and exposure to BMAA and MeHg may augment these processes.

Activation of M1 muscarinic receptors reduce pathology and slow progression of neurodegenerative disease.

The most prevalent types of dementias, including Alzheimer's disease, are those that are propagated via the spread of 'prion-like' misfolded proteins. Despite considerable effort, no treatments are available to slow or stop the progression of these dementias. Here, we investigate the possibility that activation of the M1-muscarinic receptor (M1-receptor), which is highly expressed in the brain and that shows pro-cognitive properties, might present a novel disease modifying target. We demonstrate that the progression of murine prion disease, which we show here displays many of the pathological, behavioural and biochemical hallmarks of human neurodegenerative disease, is slowed and normal behaviour maintained by the activation of the M1-receptor with a highly tolerated positive allosteric modulator (VU846). This correlates with a reduction in both neuroinflammation and indicators of mitochondrial dysregulation, as well as a normalisation in the expression of markers associated with neurodegeneration and Alzheimer′s disease. Furthermore, VU846 preserves expression of synaptic proteins and post-synaptic signalling components that are altered in disease. We conclude that allosteric regulation of M1-receptors has the potential to reduce the severity of neurodegenerative diseases caused by the ″prion-like″ propagation of misfolded protein in a manner that extends life span and maintains normal behaviour.

Creutzfeldt-Jakob Disease - a literature review

Background: Creutzfeldt-Jakob disease (CJD) is a progressive, rare, fatal and rapid human neurodegenerative disease that occurs in the etiologies: sporadic (CJD), familial, iatrogenic (CJD) and CJD variant (CJV) in which cell prion protein (PrP) can be transmitted through animals. Objectives: Literature review about Creutzfeldt-Jakob diseaseDesign and setting: Literature review development in the Centro Universitário de Volta Redonda, Rio de Janeiro, Brazil. Methods: The Creutzfeldt-Jakob disease, infectious diseases and neuroinfection indexes were used in the PUBMED and Scielo databases. Results:CJD has different etiologies with different clinical and pathological phenotypes. CJDV shows psychiatric behaviors and symptoms followed by abnormalities, ataxia and dementia. The sporadic form is the most common, with a progressive clinical course with generalized brain deposition of abnormal prion protein aggregates (PrPTSE) that leads to spongiform change, gliosis and neuronal loss. CJD progresses to dementia and two or more symptoms: cerebellar or visual impairments; pyramidal or extrapyramidal signs; myoclonus; and akinetic mutism. Complex periods of acute wave in the electroencephalogram (EEG) are strongly suggestive of prionic diseases. Rapidly evolving field neuroimmune disorders have shown an increasing in autoantibody testing; attempt to diagnose a range of immune-mediated conditions. Evidence indicates that diffusion-weighted magnetic resonance imaging (DWI) is more sensitive for detecting signal abnormalities. Conclusion: The disease progresses to dementia, accompanied by myoclonus, pyramidal signs and characteristic EEG. It is a complex pathology, which has only symptomatic treatment and requires strict control of reservoirs and risk of contamination.

Neurons Putting Out the Trash: A Novel Facet of Proteostasis and Mitochondrial Quality Control

Toxicity of misfolded proteins and mitochondrial dysfunction are pivotal factors that promote age-associated functional neuronal decline and neurodegenerative disease across species. Although these neurotoxic challenges have long been considered to be cell-intrinsic, considerable evidence now supports that misfolded human disease proteins originating in one neuron can appear in neighboring cells, a phenomenon proposed to promote pathology spread in human neurodegenerative disease. We have found that C. elegans adult neurons that express aggregating proteins can extrude large (~5µM) membrane-surrounded vesicles that can include the aggregated proteins and damaged mitochondria. We speculate that throwing out the trash may correspond to a conserved mechanism that constitutes a fundamental, but formerly unrecognized, branch of neuronal proteostasis and mitochondrial quality control. I will discuss our current understanding of the mechanisms of neuronal trash elimination.

The Application of Metabolomic Techniques in Research Investigating Neurodegenerative Diseases

We live in a world posing many new and different challenges for human health, and one such challenge is the rapidly expanding number of cases of human neurodegenerative disease [...]

Cdc48 and ubiquilins confer selective anterograde protein sorting and entry into the multivesicular body in yeast

Cdc48/p97 is known primarily for the retrotranslocation of misfolded proteins in endoplasmic reticulum (ER)-associated protein degradation (ERAD). Here we uncover a novel function for both Cdc48 and the conserved ubiquitin-associated/ubiquitin-like ubiquitin receptor (ubiquilin) proteins in yeast (e.g., Ddi1, Dsk2, and Rad23), which deliver ubiquitinated proteins to the proteasome for degradation. We show that Cdc48, its core adaptors Npl4 and Ufd1, and the ubiquilins confer the constitutive anterograde delivery of carboxypeptidase S (Cps1), a membranal hydrolase, to the multivesicular body (MVB) and vacuolar lumen. Cdc48 and Ddi1 act downstream of Rsp5-dependent Cps1 ubiquitination to facilitate the disassembly of insoluble Cps1 oligomers and upstream of ESCRT-0 to facilitate the entry of soluble protein into the MVB. Consequentially, detergent-insoluble Cps1 accumulates in cells bearing mutations in CDC48, DDI1, and all three ubiquilins (ddi1Δ, dsk2Δ, rad23Δ). Thus, Cdc48 and the ubiquilins have ERAD- and proteasome-independent functions in the anterograde delivery of specific proteins to the yeast vacuole for proteolytic activation. As Cdc48/p97 and the ubiquilins are major linkage groups associated with the onset of human neurodegenerative disease (e.g., amytrophic lateral sclerosis, Alzheimer’s, and Paget’s disease of the bone), there may be a connection between their involvement in anterograde protein sorting and disease pathogenesis.