Further information about science and technology projects at Kawasaki City is available in the Kawasaki SkyFront iNewsletter that highlights research being conducted by scientists and industries affiliated with Kawasaki INnovation Gateway at SKYFRONT (KING SKYFRONT) — the City’s flagship science and technology hub launched in 2013 to focus on open innovation in the life sciences and environment.
February 2019 issue of Kawasaki SkyFront iNewsletter
Replicating Parkinson’s disease brains in the laboratory
Stem cell technology finds its application in elucidating Parkinson’s disease using patient-derived cells
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, implicating 10 million people worldwide but has no cure at present. The main reason for this is the difficulty scientists face with replicating damage seen in the parkinsonian brain, in the laboratory. Yoshikuni Tabata, Hideyuki Okano and their team at Keio University have developed a model to understand PD better, using induced pluripotent stem cell (iPSC) technology.
iPSCs are mature cells that can be manipulated to grow into specialized cells in the body, such as kidney, liver or brain cells (neurons). This technology has been exploited in regenerative therapy. Tabata and colleagues used iPSCs derived from PD patients with a specific gene mutation (called as PARK2). The iPSCs were manipulated by a process known as differentiation, into dopaminergic neurons; the subtype of neurons which are damaged in PD. Thus, the same neurons found damaged in the patient brain, were now present in the laboratory.
The primary toxic pathway involved in PD is oxidative stress; it leads to accumulation of toxic chemicals in the neurons which endogenous antioxidants can no longer combat. The differentiated PARK2 mutant neurons, indeed had high levels of oxidative stress. They were also susceptible to death induced by exposure to rotenone, an insecticide known to damage the mitochondria and cause PD. This suggested the role of the healthy (non-mutated) PARK2 gene in maintaining oxidative balance and protecting the mitochondria.
The research team then chose a panel of drugs with varying mechanisms, to assess their effects in PARK2 related PD. Candidates were shortlisted based on their ability to protect these neurons against rotenone-induced death. A type of calcium channel antagonist, showed great promise in this regard. Such compounds stabilize calcium levels in the cell, by blocking their influx through specific channels, known as T-type calcium channels. These effects were also confirmed in another PD specific mutation (PARK6) stem cell line, showing very similar properties to PARK2. The role of the T-type calcium channels in causing neuron death in PD, thus came to light.
This study provides a promising model for mimicking the damage occurring in parkinsonian brains. The authors conclude, “this model can be used to investigate the pathogenesis of the disease and search for potential therapeutic targets for PD”. True advances can only be made once accurate depiction of any disease is achievable.
Tabata, Y. et al. T-type Calcium Channels Determine the Vulnerability of Dopaminergic Neurons to Mitochondrial Stress in Familial Parkinson Disease. Stem Cell Reports 11, 1-14 (2018)
Mapping brain function of monkeys
A novel technology has made it easier to visualize patterns in the brains of naturally behaving non-human primates
Non-human primates (NHP) have very similar social and cognitive processing to humans. Therefore, our knowledge of human behaviour can be advanced by studying the brains of NHPs. Takahiro Kondo, Hideyuki Okano and colleagues at Keio University have developed a new method of imaging neurons in the marmoset brain, a huge advancement in this field.
Traditional imaging studies on NHPs are done using head fixation, in an isolated setting. This renders it impossible to understand cognitive processes of NHPs in a natural setting. The team led by Kondo, developed a method of introducing a miniature lens into the marmoset brain, enabling them to visualize activity without the need for head fixation. For their research, the miniature lens was introduced into the motor cortex; the region responsible for planning and execution of voluntary motor movements.
After carefully mapping the motor cortex, a fluorescent calcium probe was introduced. When neurons are firing, there is influx and efflux of calcium, which can be captured with light emitted from these probes. The prism shaped lens was then fixed in after ensuring it could detect the light signal. Using their technique, up to 80-250 neurons could be captured at a time.
The device was then tested over several movement related tasks the marmosets underwent. It was observed that a subgroup of neurons was active during pulling and climbing movements, activities inherent to the animals. During periods of rest, another set of neurons showed positive calcium signals, as opposed to no activity in the motor cortex. To then study direction-based voluntary movement, the animals were presented with pellets (treats) periodically, located on either their right or left side. It was now seen that more subtypes of neurons were involved, each in the different phases of this task: before reaching for the pellet, during the actual reaching movement, and at the time of retrieval.
In their study, Kondo and co-workers highlighted the role of different neuron subtypes during naturalistic and directional voluntary movement. However, such advanced imaging will also aid in understanding neurological conditions affecting small regions of the brain, such as stroke. They positively conclude that, “This technology will make it possible to dissect large-scale neural circuits during human-relevant behaviour under natural conditions, enabling the study of complex behaviours, including social interaction, fear, and anxiety, and cognitive motor tasks”.
Kondo, T. et al. Calcium Transient Dynamics of Neural Ensembles in the Primary Motor Cortex of Naturally Behaving Monkeys. Cell Reports 24, 2191-2195 (2018).
About KING SKYFRONT
KING SKYFRONT is located on the opposite side of the Tama River that separates Tokyo International Airport (also known as Haneda Airport) and the Tonomachi district of Kawasaki. The Airport plays an important role in the globalization of the innovative activities of scholars, industrialists and City administrators based at KING SKYFRONT.
KING SKYFRONT was launched in 2013 as a base for scholars, industrialists and government administrators to work together to devise real life solutions to global issues in the life sciences and environment.
Further information :
Coastal Area International Strategy Headquarters, Kawasaki City, Japan,
1 Miyamoto-cho, Kawasaki-ku, Kawasaki-city, Kanagawa 210-8577 Japan
SOURCE KING SKYFRONT