Alpha-synuclein aggregates in Lewy bodies and Lewy neurites in Parkinson’s disease (PD) and Lewy body dementia (LBD). Neurite degeneration is a crucial step in the pathologic cascade of alpha-synuclein induced neurodegeneration. The postsynaptic mechanisms of alpha-synuclein-mediated toxicity are incompletely understood. Adult neurogenesis is decreased in transgenic animal models of synucleinopathies and alpha-synuclein impairs hippocampal neurite and spine integrity. Hippocampal cultures of alpha-synuclein transgenic mice will be used for genome profiling to investigate how gene expression signatures alter following overexpression of alpha-synuclein in neurons. Our previous experiments have identified the proteinkinase C (PKC) pathway as a key involved in alpha-synuclein induced spine integrity and this signaling pathway will be further investigated. In addition we will use a biosystemic approach and perform a comparison of the transcriptomes of hippocampal cultures to establish a gene expression-based framework to understand the molecular mechanisms of spine integrity. We will validate the array data by functional studies and follow up signaling pathways that differ between alpha-synuclein and controls. Since spine dysfunction is a common feature in LBD and PD, we will analyze if similar synaptic protein alterations in spines are also present in PD patient induced pluripotent stem cell (hiPSC) derived neurons.

Dr. Francesc Perez-Branguli

Dr. Irina Prots

Prots I, Veber V, Brey S, Campioni S, Buder K, Riek R, Böhm KJ, Winner B (2013). α-Synuclein oligomers impair neuronal microtubule-kinesin interplay. J Biol Chem 288(30):21742-54.

Winner B, Regensburger M, Schreglmann S, Boyer L, Prots I, Rockenstein E, Mante M, Zhao C, Winkler J, Masliah E, Gage FH (2012). Role of α-synuclein in adult neurogenesis and neuronal maturation in the dentate gyrus. J Neurosci 32(47):16906-16. 

Regensburger M, Prots I, Winner B (2014). Adult Hippocampal Neurogenesis in Parkinson's Disease: Impact on Neuronal Survival and Plasticity. Neural Plast 2014:454696. 

Purohit P, Perez-Branguli F, Prots I, Borger E, Gunn-Moore F, Welzel O, Loy K, Wenzel EM, Grömer TW, Brachs S, Holzer M, Buslei R, Fritsch K, Regensburger M, Böhm KJ, Winner B, Mielenz D (2014). The Ca2+ Sensor Protein Swiprosin-1/EFhd2 Is Present in Neurites and Involved in Kinesin-Mediated Transport in Neurons. PLoS One 9(8):e103976.

Franz S, Ciatipis M, Pfeifer K, Kierdorf B, Sandner B, Bogdahn U, Blesch A, Winner B, Weidner N (2014). Thoracic rat spinal cord contusion injury induces remote spinal gliogenesis but not neurogenesis or gliogenesis in the brain. PLoS One 9(7):e102896.

Ettle B, Reiprich S, Deusser J, Schlachetzki JC, Xiang W, Prots I, Masliah E, Winner B, Wegner M, Winkler J (2014). Intracellular alpha-synuclein affects early maturation of primary oligodendrocyte progenitor cells. Mol Cell Neurosci 62:68-78.

Pérez-Brangulí F, Mishra HK, Prots I, Havlicek S, Kohl Z, Saul D, Rummel C, Dorca-Arevalo J, Regensburger M, Graef D, Sock E, Blasi J, Groemer TW, Schlötzer-Schrehardt U, Winkler J, Winner B (2014). Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia. Hum Mol Genet 23(18):4859-74.

Havlicek S, Kohl Z, Mishra HK, Prots I, Eberhardt E, Denguir N, Wend H, Plötz S, Boyer L, Marchetto MC, Aigner S, Sticht H, Groemer TW, Hehr U, Lampert A, Schlötzer-Schrehardt U, Winkler J, Gage FH, Winner B (2014). Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients' neurons. Hum Mol Genet 23(10):2527-41.

Rockenstein E, Nuber S, Overk CR, Ubhi K, Mante M, Patrick C, Adame A, Trejo-Morales M, Gerez J, Picotti P, Jensen PH, Campioni S, Riek R, Winkler J, Gage FH, Winner B, Masliah E (2014). Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo. Brain 137(Pt 5):1496-513. 

Winner B, Marchetto MC, Winkler J, Gage FH (2014). Human-induced pluripotent stem cells pave the road for a better understanding of motor neuron disease. Hum Mol Genet 23(R1):R27-R34.

1. Winner B, Jappelli R, Maji SK, Desplats P, Boyer L, Aigner S, Hetzer C, Loher T, Vilar M, Campioni S, Tzitzilonis C, Soragni A, Jessberger S, Mira H, Consiglio A, Pham E, Masliah E, Gage FH and Riek R. In vivo demonstration that a-synuclein oligomers are toxic. PNAS 2011; 108(10):4194-9.

2. Winner B, Melrose HL, Zhao C, Hinkle KM, Yue M, Kent C, Braithwaite AT, Ogholikhan S, Aigner R, Winkler J, Farrer MJ, Gage FH. Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice. Neurobiol Dis. 2011; 41(3):706-16.

3. Marchetto MC, Winner B, Gage FH. Pluripotent stem cells in neurodegenerative and neurodevelopmental diseases. Hum Mol Genet. 2010; R71–R76.

4. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanism underlying inflammation in neurodegeneration. Cell. 2010; 19;140(6):918-34.

5. Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK. A Nurr1/CoREST transrepression pathway antagonizes neurotoxicity of activated microglia, Cell. 2009; 137: 47-59.

6. Marxreiter F, Nuber S, Klucken J, Aigner R, Burgmayer R, Couillard-Despres S, Riess O, Winkler J, and Winner B, A30P alpha-synuclein expression regulates adult olfactory bulb neurogenesis. Eur J Neurosci, 2009; 29, 879–890.

7. Crews L, Mizuno H, Desplats P, Rockenstein E, Adame A, Winner B, Winkler J, Masliah E, α-Synuclein alters Notch-1 expression and neurogenesis in mouse embryonic stem cells and in the hippocampus of transgenic mice. J Neurosci 2008; 16;28(16):4250-60.

8. Winner B, Lie DC, Rockenstein E, Aigner R, Aigner L, Masliah E, Kuhn HG, Winkler J. Human wild-type alpha-synuclein impairs neurogenesis. J Neuropathol Exp Neurol 2004; 63: 1155-66.

9. Pérez-Brangulí F, Cotrufo T, Muhaisen A, Ros O , Andrés R, Baeriswyl A, Fuschini G, Tarrago T, Pascual M, Ureña J, Comella J, Giralt E, Blasi J, Stoeckli E, Soriano E. A signaling mechanism coupling Netrin1/DCC chemoattraction to SNARE-mediated exocytosis in growth cones. Journal of Neuroscience, 2011; 31(41):14463-80.

10. Janssen BJ, Robinson RA, Pérez-Brangulí F, Bell CH, Mitchell KJ, Sielbold C, Jones EY. Structural basis of semaphoring-plexin signalling. Nature, 2010; 467,1118-22.