- Aug. 23, 2017
Niche-derived laminin-511 promotes midbrain dopaminergic neuron survival and differentiation through YAP
Zhang D, et al.
Parkinson’s disease (PD) is a neurodegenerative disorder marked by progressive loss of dopaminergic neurons and motor control. Various factors promote or inhibit neuronal survival. Zhang et al. found that a prosurvival signal was mediated by the transcription cofactor YAP. YAP was activated in midbrain dopaminergic neurons in culture and in mice through an interaction between an integrin and the extracellular matrix protein laminin-511. YAP then transcriptionally activated dopaminergic neuron differentiation factors and a microRNA that decreased the synthesis of the apoptotic protein PTEN. The findings uncover a new role for YAP in neurons and a pathway that might be explored for the purpose of promoting dopaminergic neuron survival in PD patients.
- Jul. 13, 2017
A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway
Salašová A, et al.
Autosomal-dominant mutations in the Park8 gene encoding Leucine-rich repeat kinase 2 (LRRK2) have been identified to cause up to 40% of the genetic forms of Parkinson’s disease. However, the function and molecular pathways regulated by LRRK2 are largely unknown. It has been shown that LRRK2 serves as a scaffold during activation of WNT/β-catenin signaling via its interaction with the β-catenin destruction complex, DVL1-3 and LRP6. In this study, we examine whether LRRK2 also interacts with signaling components of the WNT/Planar Cell Polarity (WNT/PCP) pathway, which controls the maturation of substantia nigra dopaminergic neurons, the main cell type lost in Parkinson’s disease patients.
- Jul. 3, 2017
- Jun 26, 2017
Molecular analysis of the midbrain dopaminergic niche during neurogenesis
Toledo EM, et al.
Midbrain dopaminergic (mDA) neurons degenerate in Parkinson's disease and are one of the main targets for cell replacement therapies. However, a comprehensive view of the signals and cell types contributing to mDA neurogenesis is not yet available. By analyzing the transcriptome of the mouse ventral midbrain at a tissue and single-cell level during mDA neurogenesis we found that three recently identified radial glia types 1-3 (Rgl1-3) contribute to different key aspects of mDA neurogenesis. While Rgl3 expressed most extracellular matrix components and multiple ligands for various pathways controlling mDA neuron development, such as Wnt and Shh, Rgl1-2 expressed most receptors. Moreover, we found that specific transcription factor networks explain the transcriptome and suggest a function for each individual radial glia. A network controlling neurogenesis was found in Rgl1, progenitor maintenance in Rgl2 and the secretion of factors forming the mDA niche by Rgl3. Our results thus uncover a broad repertoire of developmental signals expressed by each midbrain cell type during mDA neurogenesis. Cells identified for their emerging importance are Rgl3, a niche cell type, and Rgl1, a neurogenic progenitor that expresses ARNTL, a transcription factor that we find is required for mDA neurogenesis.
- May 26, 2017
Translation of WNT developmental programs into stem cell replacement strategies for the treatment of Parkinson's disease
Toledo EM, Gyllborg D, and Arenas E
- May 9, 2017
- Apr. 19, 2017
Mapping Genes for Calcium Signaling and Their Associated Human Genetic Disorders
Hörtenhuber M. et al.
- Apr. 17, 2017
- Apr. 10, 2017
Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model
Rivetti di Val Cervo P, et al.
Cell replacement therapies for neurodegenerative disease have focused on transplantation of the cell types affected by the pathological process. Here we describe an alternative strategy for Parkinson's disease in which dopamine neurons are generated by direct conversion of astrocytes. Using three transcription factors, NEUROD1, ASCL1 and LMX1A, and the microRNA miR218, collectively designated NeAL218, we reprogram human astrocytes in vitro, and mouse astrocytes in vivo, into induced dopamine neurons (iDANs). Reprogramming efficiency in vitro is improved by small molecules that promote chromatin remodeling and activate the TGFβ, Shh and Wnt signaling pathways. The reprogramming efficiency of human astrocytes reaches up to 16%, resulting in iDANs with appropriate midbrain markers and excitability. In a mouse model of Parkinson's disease, NeAL218 alone reprograms adult striatal astrocytes into iDANs that are excitable and correct some aspects of motor behavior in vivo, including gait impairments. With further optimization, this approach may enable clinical therapies for Parkinson's disease by delivery of genes rather than cells.
- Oct. 6, 2016
Molecular Diversity of Midbrain Development in Mouse, Human, and Stem Cells
La Manno G, Gyllborg D, et al.
Understanding human embryonic ventral midbrain is of major interest for Parkinson’s disease. However, the cell types, their gene expression dynamics, and their relationship to commonly used rodent models remain to be defined. We performed single-cell RNA sequencing to examine ventral midbrain development in human and mouse. We found 25 molecularly defined human cell types, including five subtypes of radial glia-like cells and four progenitors. In the mouse, two mature fetal dopaminergic neuron subtypes diversified into five adult classes during postnatal development. Cell types and gene expression were generally conserved across species, but with clear differences in cell proliferation, developmental timing, and dopaminergic neuron development. Additionally, we developed a method to quantitatively assess the fidelity of dopaminergic neurons derived from human pluripotent stem cells, at a single-cell level. Thus, our study provides insight into the molecular programs controlling human midbrain development and provides a foundation for the development of cell replacement therapies.
- Sep. 15, 2016
A PBX1 transcriptional network controls dopaminergic neuron development and is impaired in Parkinson's disease
Villaescusa JC, et al.
Pre‐B‐cell leukemia homeobox (PBX) transcription factors are known to regulate organogenesis, but their molecular targets and function in midbrain dopaminergic neurons (mDAn) as well as their role in neurodegenerative diseases are unknown. Here, we show that PBX1 controls a novel transcriptional network required for mDAn specification and survival, which is sufficient to generate mDAn from human stem cells. Mechanistically, PBX1 plays a dual role in transcription by directly repressing or activating genes, such as Onecut2 to inhibit lateral fates during embryogenesis, Pitx3 to promote mDAn development, and Nfe2l1 to protect from oxidative stress. Notably, PBX1 and NFE2L1 levels are severely reduced in dopaminergic neurons of the substantia nigra of Parkinson's disease (PD) patients and decreased NFE2L1 levels increases damage by oxidative stress in human midbrain cells. Thus, our results reveal novel roles for PBX1 and its transcriptional network in mDAn development and PD, opening the door for new therapeutic interventions.
About the lab:
The Arenas Laboratory aims at developing regenerative therapies for Parkinson's disease. Work in this area integrates molecular, cellular, and biochemical techniques, and involves both in vitro and in vivo studies. Of particular interest are specific aspects of midbrain and dopamine neuron development, Wnt signaling, biotechnology, stem cell biology and regenerative medicine for Parkinson's disease.
At Karolinska Institutet, the laboratory is situated in the Retzius laboratories within the division of Molecular Neurobiology at the Department of Medical Biochemistry and Biophysics (MBB). MBB is a department consisting of 12 research divisions within the fields of protein chemistry, redox biochemistry, metabolism, lipid research, inflammation research, structural biochemistry, molecular biochemistry, tissue biology, and developmental biology.
Karolinska Institutet is Sweden’s single largest centre of medical academic research and one of the world’s foremost medical universities with a vision is to make a significant contribution to the improvement of human health. Since 1901 the Nobel Assembly at Karolinska Institutet awards the Nobel prize in Physiology or Medicine.