What is Neurodegenerative Disease?
Diseases that affect body activities such as walking, talking, breathing and also involuntary actions such as heartbeat and kidney functioning are called neurodegenerative diseases. These diseases are most common in senior citizens but are also prevalent in children with premature births. Some examples of this disease are Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). The World Health Organization (WHO) predicts that NDD will become the second leading cause of death after cardiovascular disease by 2040. There is an increasing need for more animal models that can outline the complexity of NND pathogenesis. Movement disorders are a heterogeneous group of neurological conditions characterized by the inability to produce or control movement. The typical clinical features include either paucity of voluntary movements, referred to as hypokinesia, bradykinesia and akinesia, or excess of movement, commonly denoted as hyperkinesia, dyskinesia, and abnormal involuntary movements. These two major groups have been dynamic, including different categories over time. Most movement disorders lack effective pharmacological therapies, because their complex etiology and pathological mechanisms remain largely unknown.
Why Zebrafish can be an effective animal model for neurodegenerative disease?
- Due to the transparency feature that is observed in zebrafish embryos, visualization of individual genes (fluorescently labeled or dyed) are possible through non-invasive imaging techniques. This transparency of the embryo also helps in genetic manipulations.
- Neuroactive compounds can also be screened through High-throughput methods due to the small size of larvae.
Mode of Induction In Zebrafish:
It is very easy to introduce transient manipulation of gene activities and their subsequent examination in a normal cellular environment. The embryos are quite malleable to genetic manipulation by morpholino antisense oligonucleotide, mRNAs, transgenes and genome editing techniques like CRISPR-Cas9, TALENS.
Parameters to analyze neurotoxicity using behavior related assays:
1) Spontaneous Coil Test (STC):
The test is to measure coiling activity was evaluated in terms of coil duration and coiling frequency. Exposure duration should be in the range of 0–28 hpf and the age of the embryo at the time of measurement must be 19–28 hpf.
2) Photomotor response test (PMR):
Embryos were exposed in crystallizing dishes from 2 to ~30-35 hpf at 26°C. Embryos at this stage were then subjected to PMR measurements. Movement activity or motion index are recorded. Exposure duration should be in the range of 0–28 hpf and the age of the embryo at the time of measurement must be 19–28 hpf.
3) Locomotor response test (LMR):
Locomotor activity was recorded in terms of total distance moved and was integrated every single minute for each treatment (T) and control group (C) (n = 16 embryos each). Exposure duration should be in the range of 0–120 hpf and the age of the embryo at the time of measurement must be 72–120 hpf.
4) Alternating light- and dark-induced locomotor response test (LMR-L/D):
The test places the embryo in a 10-min period of darkness followed by three alternating cycles of 10-min light and 10-min dark. The swimming distance, duration, and speed are recorded. Exposure duration should be in the range of 0–120 hpf and the age of the embryo at the time of measurement must be 72–120 hpf.
- The treatment for neurodegenerative diseases with neuroactive substances should give the following outcomes
- Similar behavioral methods resulted in a consistent behavioral response across studies with regard to anticipated activity (hypo- or hyperactivity),
- Different methods (STC, PMR, LMR, LMR-L/D) should give consistent anticipated activity (hypo- or hyperactivity),
- The observed activity was consistent with the anticipated activity regardless of the method used,
- The respective effect concentrations in the different studies are similar—in cases when hypo- or hyperactivity is consistent between the studies.
- A number of pharmacological drugs designed for neurodegenerative diseases treatment have failed in clinical trials over the past several decades due to the clinical heterogeneity of the disease. In addition, disease-modifying treatments can only be effective in the early stage of the disease because most NDD pathologies are irreversible.