Alexander Storch

Clinical and experimental neuroregeneration in Parkinson’s disease

Previous and current research

Neural stem cells (NSCs) are a subtype of tissue-specific progenitor cells that is capable of extended self-renewal and the ability to generate all major cell types of nervous tissue, such as neurons, astroglia and oligodendroglial cells. Recent studies suggest that salient pattering in anterior-posterior and dorsal-ventral axes occurs early, concomitantly with neural induction and therefore stem cells and restricted precursors exhibit regionalization. Fetal midbrain NSCs can be isolated and long-term expanded in vitro for many months while retaining the potential to differentiate into glia and neurons with a subset of neurons displaying all major properties of mature functional dopaminergic neurons. Since Parkinson’s disease (PD) is characterized by the loss of a specific type of dopaminergic cells in PD the prospect of replacing the missing or damaged cells is very attractive. Thus, mesencephalic NSCs might serve as a new and continuous source of dopaminergic neurons for transplantation strategies in this neurodegenerative disorder. Moreover, recent studies reported the presence of quiescent multipotent NSCs within the adult rodent midbrain, the region where the neurodegeneration in PD is located, with the potential to differentiate into functional dopaminergic nerve cells. These findings are a major prerequisite for the establishment of regenerative approaches by recruiting endogenous stem cells in PD. The presentation discusses new data on the cellular biology as well as the therapeutic potential of NSCs derived from the midbrain region of the CNS.

We currently characterize adult and fetal midbrain neural stem cells both in vivo and in vitro with respect to their proliferation and differentiation potential, and we try to re-activate the quiescent adult stem within the adult midbrain region.

Figure: Characteristics of midbrain neural stem cells in vitro expansion. A, Morphology and marker expression of adult tNSCs during expansion in the presence of EGF and FGF-2. B, Neuronal subtype differentiation capacity of tNSCs in vitro established by using differentiation protocols 2 to 4 after an expansion phase of 3 to 12 weeks. Triple immunostaining of tNSCs differentiated using protocol 4 for markers of astroglia (GFAP), neurons (Tuj1) and oligodendroglia (GalC), as well as cholinergic (ChAT), GABAergic (GABA), glutamatergic (glutamate) and dopaminergic (TH) neurons. Nuclei were counterstained with DAPI (blue). Arrows mark double stained neurons. The inset shows high magnification confocal image of a Tuj1+/TH+ neuron. Scale bars, 30 µm (left panel) or 15 µm. C, Neurotransmitter (dopamine, GABA) production and release of tNSCs differentiated on PA6 cells using protocol 4. Left panel: Representative chromatograms of HPLC-ECD determination of dopamine in medium conditioned for 2 days by tNSCs on PA6 cells (protocol 4, red) and PA6 cells alone (blue). Standard is presented in green. Right panel: Quantification of dopamine and GABA production in medium conditioned for 2 days (blue bars), in extracellular buffer conditioned for 45 min. (red bars), and in extracellular buffer + 56 mM KCl conditioned for 45 min. (green bars). D, Electrophysiological properties of adult tegmental NSCs differentiated using protocol 1 for 10 days.

Future prospects and goals

Identification of molecular targets to regulate mesencephalic neural stem cells behaviour in vitro and in vivo. Thus, we currently identify intracellular signaling pathways during dopaminergic specification of mesencephalic stem cells. Furthermore, within a CRTD project we try to establish a new transplantation therapy for Parkinson’s disease (the so-called „bridging transplantation“) by combining orthotopic transplantation of dopaminergic cells into the substantia nigra and targeted axonal outgrowth of the transplanted cells to the target area, the striatum. This appraoch has the great advantage of potential reconstruction and synaptic integration of the nigro-striatal pathway into the host brain.

About

2001: Habilitation in Neurology, University of Ulm, Ulm - Germany 2001: Board certification in Neurology 2004: Board certification in Clinical Geriatrics 1996-1996: Research assistant, Laboratory of Molecular Neurobiology, Institute of Physiological Chemistry, University of Mainz, Germany 1996–2001: Internship and residency, Department of Neurology and at the Department of Psychiatry, University of Ulm, Germany 1998–1998: Research Associate at the Departments of Pharmacology and Neurological Sciences, Rush-University Medical Center, Chicago - USA 2001-2004: Senior neurologist and group leader of the Movement Disorder Outpatient Clinic at the Department of Neurology, University of Ulm, Germany since 2004: Professsor of Neurodegenerative Disorders and group leader of the Movement Disorder Outpatient Clinic at the Department of Neurology, TU Dresden

Selected publications

Sabolek M, Baumann B, Heinrich M, Meyer AK, Herborg A, Liebau S, Maisel M, Hermann A, Herr A, Schwarz J, Wirth T, Storch A, 2009, Initiation of dopaminergic differentiation of mesencephalic precursor cells by interleukin-1b depends on activation of multiple MAP kinase pathways, Stem Cells 27(8): 2009-2021

Hermann A, Suess C, Fauser M, Kanzler S, Witt M, Fabel K, Schwarz J, Höglinger GU, Storch A, 2009, Rostro-caudal gradual loss of cellular diversity within the periventricular regions of the ventricular system, Stem Cells 27(4): 928-941

Weber YG^$, Storch A^$, Wuttke T^$, Brockmann K, Kempfle J, Maljevic S, Margari L, Kamm C, Schneider SA, Huber SM, Pekrun A, Roebling R, Seebohm G, Koka S, Lang C, Kraft E, Blazevic D, Salvo-Vargas A, Fauler M, Mottaghy F, Münchau A, Edwards MJ, Presicci A, Margari F, Gasser T, Lang F, Bhatia KP, Lehmann-Horn F, Lerche H, 2008, GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak, J. Clin. Invest. 118(6): 2157-2168 (IF: 16.559) 

^$ contributed equally to this study

Hermann A, Maisel M, Wegner F, Liebau S, Kim D-W, Gerlach M, Schwarz J, Kim K-S, Storch A, 2006, Multipotent neural stem cells from the adult tegmentum with dopaminergic potential develop essential properties of functional neurons, Stem Cells 24: 949-964

Hermann A, Gastl R, Liebau S, Popa MO, Fiedler J, Böhm BO, Maisel M, Lerche H, Schwarz J, Brenner R, Storch A, 2004, Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells, J. Cell Sci. 117: 4411-4422

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