News

Much insight into the brain’s function has been gained from scientists working with animal models. However, animal models have their limitations since animal brains undergo a very different development process to humans brains. Some research has been carried out on the human brain, but it has relied on post-mortem donations and cultured cells. Since human brain tissue is difficult to obtain and animal models can only model the human brain to a limited extent, there was a crucial gap in brain research and a novel method to model human disease was highly sought after.

The Cappello research group at the Max Planck Institute of Psychiatry in a highly collaborative work, particularly with the laboratory of Barbara Treutlein from the Max Planck Institute for Evolutionary Anthropology in Leipzig, have employed brain organoids to model developmental brain malfunctions. These brain organoids have revolutionized neuroscience as they can recapitulate the way neurons differentiate in development to a remarkably high degree. When the human brain develops, new cells grow and aggregate in a very specific order.

The brain organoids in this study were grown from skin cell biopsies donated by patients. Silvia Cappello, who leads the work, explains: “We reprogrammed the skin cells into induced pluripotent stem cells. These pluripotent stem cells were then used to generate brain cells, which could be differentiated into many different types of brain cells.” The different types of brain cells and their interactions can then be studied behaving in a way they would in an actual human brain. Cappello adds: “Brain organoids give us a much clearer picture of how brain cells are functioning and can accurately model human neurological diseases.”

The ability to model human brain development in vitro holds tremendous translational value. Brain organoids have already helped scientists to better understand the Zika virus, Alzheimer’s disease and autism. As the brain organoid is grown from the cells of an individual, it allows scientists to study exactly what is happening in individual patients. Cappello concludes: “Validating brain organoids represents a hugely important step in helping us to understand developmental and neurological disorders and they hold great promise for discovering new treatments.”

read more

Our world is full of sensory stimuli. Depending on what we see, smell, taste, feel, or hear, we are compelled to behave in a predictable way – like approaching tasty food or avoiding an oncoming car. The brain’s ability to make sense of the diverse sensory stimuli and to coordinate the appropriate behavioral response relies critically on the function of the cerebellum. This hindbrain region, critical to sensorimotor coordination, is conserved across vertebrates, from humans to birds to fish.

The mammalian cerebellum, however, contains hundreds of thousands of Purkinje cells, each receiving inputs from many thousands of presynaptic neurons. Cracking the cerebellar code here is nearly impossible, even with the latest methods. Ruben Portugues and his team thus focus on a "simpler" version: the cerebellum of six to eight day old zebrafish larvae.

“At this age, the zebrafish cerebellum contains about 500 Purkinje cells and is involved in behaviors such as swimming and eye movements”, explains Laura Knogler, who studied the cerebellar circuits together with graduate student Andreas Kist. “It’s all there and still very complex, but we have a chance to see all cells’ activity in the transparent brains of these fish and directly record the detailed activity of individual cells.” By studying the cerebellum of zebrafish larvae behaving within virtual-reality environments, the scientists were now able to tackle the central question of how the cerebellum coordinates behavior.

Like many vertebrates, zebrafish use visual cues to direct their movements, keep track of their environment or to identify potential predators or prey. Using this knowledge, the neuroscientists showed the fish different visual stimuli while observing neuronal activity and the motor functions. The surprising result was a cerebellar division into three behavioral modules, each encoding a distinct type of visual information: directional motion onset, rotational motion velocity, or changes in luminance. Every studied Purkinje cell belonged to one of these three modules.

In contrast, the behavior of the fish was encoded in nearly the same way by all cells. This became visible in an impressive way when the fish were swimming: “Nearly the entire cerebellum lit up with fluorescence, showing an overwhelming amount of Purkinje cell excitation during swim bouts”, relates Andreas Kist. The scientists believe that the observed cerebellar organization is an important trait for neural coding and associative learning: “The modules appeared optimized to organize the information necessary for the principal behaviors of the zebrafish at this age, yet may also allow for the flexibility required to learn new things through experience”, explains Knogler. “I wouldn’t be surprised if other sensory input and the cerebella of other species are organized in a similar way.”.

read more

One in four people in Western and Asian societies develop a build-up of fat in the liver as a result of an unhealthy diet. This disease – referred to as non-alcoholic fatty liver disease (NAFLD) – causes no symptoms initially but can develop into end-stage liver cirrhosis with limited treatment options. A discovery, published today in Molecular Systems Biology, paves the way for a simple blood test to detect early stages of NAFLD, opening up the possibility of preventing the development of liver cirrhosis through lifestyle changes or pharmaceutical intervention.

The liver is an important organ, filtering toxic substances from the body and producing proteins required for digestion, blood clotting, and other important physiological functions. “The liver is very resilient and capable of regenerating itself, which may be the reason why liver damages due to excessive fat deposition can go undetected for a long time,” says EMBO Member Matthias Mann of the Max Planck Institute of Biochemistry in Martinsried, Germany, and the University of Copenhagen, Denmark, who led the study. However, when damage accumulates liver function eventually starts to fail.

To date, the standard procedure for diagnosing NAFLD is liver biopsy – a cumbersome and costly procedure that can lead to complications. Non-invasive methods that reliably detect early stage NAFLD are therefore urgently required.

Matthias Mann and his colleagues investigated the plasma proteome – the entire set of proteins present in the blood plasma – of NAFLD patients. Using sophisticated mass spectrometry technologies, they uncovered a set of proteins that accumulate in the plasma of patients with non-symptomatic NAFLD.

read more

Cosolo, A., Jaiswal, J., Csordas, G., Grass, I., Uhlirova, M., and Classen, A.K.
Elife 8, 2019.
doi: 10.7554/eLife.41036

JNK-dependent cell cycle stalling in G2 promotes survival and senescence-like phenotypes in tissue stress

The restoration of homeostasis after tissue damage relies on proper spatial-temporal control of damage-induced apoptosis and compensatory proliferation. In Drosophila imaginal discs these processes are coordinated by the stress response pathway JNK. We demonstrate that JNK signaling induces a dose-dependent extension of G2 in tissue damage and tumors, resulting in either transient stalling or a prolonged but reversible cell cycle arrest. G2-stalling is mediated by downregulation of the G2/M-specific phosphatase String(Stg)/Cdc25. Ectopic expression of stg is sufficient to suppress G2-stalling and reveals roles for stalling in survival, proliferation and paracrine signaling. G2-stalling protects cells from JNK-induced apoptosis, but under chronic conditions, reduces proliferative potential of JNK-signaling cells while promoting non-autonomous proliferation. Thus, transient cell cycle stalling in G2 has key roles in wound healing but becomes detrimental upon chronic JNK overstimulation, with important implications for chronic wound healing pathologies or tumorigenic transformation.