Biology subjects

Piepponen, T. P.

Publications and source records attributed to Piepponen, T. P..

3 recordsLinked to original sources

bioRxiv2024

Serotonin system development and adult function are regulated by GDNF

Cognitive functions, neuropsychiatric disorders and behaviors from feeding to mood relate to the serotonin (5-hydroxytryptamine; 5-HT) system. We report that expression of glial cell line-derived neurotrophic factor (GDNF), a known potent stimulator of the brain dopamine system, correlates with serotonergic markers in humans, and increased GDNF defines a subset of psychiatric patients with a characteristic 5-HT-related gene expression pattern. A similar [~]1.5- to 2-fold upregulation of endogenous GDNF expression in mice increases brain 5-HT levels and function, both developmentally and during adulthood, and modulates response to fluoxetine. Notably, increasing GDNF more than approximately 2-fold does not increase 5-HT further and instead produces an inverted U-shaped curve of 5-HT levels, suggesting why the GDNF/5-HT correlation has remained controversial. Collectively, our data indicate that GDNF levels fine-tune 5-HT system development and adult function while excess GDNF exclusively associates with neuropsychiatric illness, making it an important target for future research.

neuroscience↗

bioRxiv2019

Gene Knock Up via 3’UTR editing to study gene function in vivo

Currently available genetic tools do not allow researchers to upregulate ( Knock Up) the levels of a given protein while retaining its cell-type-specific regulation. As a result, we have limited ability to develop overexpression-related disease models, to study the contribution of single genes in diseases caused by copy number variations and to identify disease pathways for drug targets. Here we develop two approaches for endogenous gene upregulation: conditional Knock Up (cKU) utilizing the Cre/lox system, and CRISPR-Cas9 mediated gene Knock Up (KU) in wild-type mouse embryos and human cells. Using glial cell line derived neurotrophic factor (GDNF) as a proof of concept, we show that both approaches resulted in upregulation of endogenous GDNF levels without disturbing Gdnfs expression pattern. Furthermore, CNS-specific GDNF cKU resulted in dopaminergic abnormalities and schizophrenia-like phenotypes. Our results suggest that gene Knock Up can reveal unknown gene functions and provide novel entry points for studying neurological disease.

neuroscience↗

bioRxiv2019

GDNF receptor agonist supports dopamine neurons in vitro and protects their function in animal model of Parkinson's disease.

Motor symptoms of Parkinsons disease (PD) are caused by degeneration and progressive loss of nigrostriatal dopamine neurons. Currently no cure for this disease is available. Existing drugs alleviate PD symptoms, but fail to halt neurodegeneration. Glial cell line-derived neurotrophic factor (GDNF) is able to protect and repair dopamine neurons in vitro and in animal models of PD, but its clinical use is complicated by pharmacokinetic properties. In the present study we demonstrate the ability of a small molecule agonist of GDNF receptor RET to support the survival of cultured dopamine neurons only when they express GDNF receptors. In addition, BT13 activates intracellular signaling cascades in vivo, stimulates release of dopamine and protect the function of dopaminergic neurons in a 6-hydroxydopamine (6-OHDA) rat model of PD. In contrast to GDNF, BT13 is able to penetrate through the blood-brain-barrier. Thus, BT13 serves as an excellent tool compound for the development of novel disease-modifying treatments against PD.

neuroscience↗