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HelMA scientific highlights 2010

Another successful year of HelMA research yielded a wealth of new results

The HelMA Alliance can look back on another successful year – again, in 2010 the main scientific achievements obtained by HelMA researchers mirror the successful integrative, disease- and discipline-spanning approach and resulted in 90 HelMA-associated publications.

 

In the field of Alzheimer’s disease (AD), partners within the HelMA consortium continued their successful work on deciphering the involvement of SorLA and sortilin (both receptors of the LDL family) in the pathoetiology of AD. This provided important new insights into pathways underlying the profound effects of lipid metabolism as a risk factor in neurodegenerative disorders 1,2,3. The strong connection between disturbed lipid homeostasis and the etiology of AD was also evaluated within the clinics groups. For example, serum lipid levels in patients with SNPs (Single Nucleotide Polymorphism) in four different loci associated with AD were found to be significantly altered 4.

 

An influence of other dietary components on the disease course of AD (as well as Parkinson’s disease, PD) could be further substantiated. It has for example been shown that small molecules – such as EGCG (a component of green tea extract) - can be used to redirect toxic amyloidogenic polypeptides into non-toxic structures that are efficiently degraded by mammalian cells. Furthermore, EGCG is even able to disassemble preformed β-sheet-rich amyloid fibrils yielding smaller, amorphous protein aggregates that are non-toxic for mammalian cells5. This makes EGCG and/or related small molecules suitable model substances for potential therapeutics. Another therapeutic approach (evaluating novel drug targets) is the identification of regulative elements of nonamyloidogenic processing of βAPP, revealing that deletion of the ER-retention signal (identified in a collaborative work of HelMA researchers6) in ADAM10 increased the non-amyloidogenic processing of βAPP.

 

Also in the field of Parkinson research, HelMA could continue and expand its scientific success – main risk factors for sporadic PD could be confirmed, and additional new loci associated with the risk of developing PD identified Nalls et al., submitted (The Lancet). Another step forward was taken in identifying putative molecular mechanisms underlying endophenotypes 7, 8. In sum, these studies support the idea approached in HelMA, that analogous but not fully identical molecular mechanisms might underlie the pathogenesis of different neurodegenerative diseases.

 

Following this concept of analogous molecular mechanisms, some HelMA researchers concentrated on pathways associated with the dysfunction of mitochondria and the cytoskeleton.9,10,11 Indeed, mitochondrial fragmentation as an indicator of mitochondrial impairment observed in vitro becomes efficiently and fully compensated over time and in vivo9; Glasl et al, submitted. This indicates that animals and possibly also humans can compensate for the single dysfunction of a gene, and thus a certain genetic background or environmental influences are the decisive factors in case no compensation takes place.

 

Concerning cytoskeletal dysfunction, HelMA researchers successfully identified the interactome of LRRK2 showing that it is highly likely involved in the regulation of the actin cytoskeleton. The published dataset12 was nominated “Dataset of the month November 2010” by the EMBL-European Bioinformatics Institute. In addition, due to the changed cytoskeletal dynamics, a major cellular phenotype induced by LRRK2 knock-down is the alteration of neuronal morphology – a phenotype again representing a common theme in distinct neurodegenerative diseases which also has been demonstrated by HelMA researchers13.

 

Within the disease spanning therapy development on the basis of stem cells (regenerative medicine), HelMA scientists made important steps towards understanding the mechanisms underlying the generation and maintenance of new neurons in the adult brain have been made. 14, 15, 16 The work on full reprogramming of adult astrocytes into neurons has been completed17 and the protocol for instructing neurogenesis from glial cells has been published.18 Major progress has also been obtained within the disease-spanning themes comorbidity and systems biology. Specifically the behavioural analysis of different mouse models at different ages yielded impressive results. The applied comprehensive test battery encompassing motor-, cognitive, anxiety-related and olfactory phenotypes revealed for example that the genetic animal models of PD examined (DJ-1; Pink1, and LRRK2) exhibit gait impairments at old ages – despite the non-appearance of age related neurodegeneration of the dopaminergic system. Furthermore, gene- but not age-associated distinct non-motoric symptoms such as olfactory deficits, impairment in cognition and anxiety-related phenotypes have been revealed.

 

Besides investigating disease specific networks using bioinformatics tools, which contributed significantly to publications (e.g. the validation of the regulation of Parkin expression via the ATF4 transcription factor19 or the identification of transcription factor binding site modules in Alzheimer’s diseaseAugustin et al., in press), this work contributed substantially to the identification of shared pathways between AD and PD and with pathways elicited by acute stress. Indeed, based on bioinformatic analysis, novel networks in the PVN, involving stress-regulated genes have been revealed.20. This work once again hints towards an involvement of stress-regulated pathways in the etiology of neurodegenerative diseases, an issue which will be followed up in the upcoming funding period by several groups.

 

Overall, the HelMA consortium is highly motivated by the success of the past and looking forward to another exciting and scientifically flourishing year.

 

Cited references:

1 Kjolby M, Andersen OM, Breiderhoff T, Fjorback AW, Pedersen KM, Madsen P, Jansen P, Heeren J, Willnow TE, Nykjaer A (2010). Sort1, encoded by the cardiovascular risk locus 1p13.3, is a novel regulator of hepatic lipoprotein export. Cell Metab. 12: 213-223. http://www.ncbi.nlm.nih.gov/pubmed/20816088

2 Willnow TE, Carlo AS, Rohe M, Schmidt V (2009). SORLA/SORL1, a neuronal sorting receptor implicated in Alzheimer's disease. Rev Neurosci. 2010;21(4):315-29. http://www.ncbi.nlm.nih.gov/pubmed/21086763

3 Vaegter CB, Jansen P, Fjorback AW, Glerup S, Skeldal S, Richner M, Erdmann B, Raarup MK, Nyengaard JR, Tessarollo L, Lewin GR, Willnow TE, Chao MV, Nykjaer A (2010). Sortilin anterogradely traffics Trk receptors and stimulate signaling by mature neurotrophins. Nat. Neurosci. (in press).

4 Feulner TM, Riehle C, Gasparoni G, Schiller C, Wagenpfeil S, Wurst SH, Mayhaus M and Riemenschneider M. Genome wide association study of recently found new Alzheimer candidate genes PICALM, CLU, CR1 and BIN1 in a German cohort. (submitted).

5 Bieschke J, Russ J, Friedrich RP, Ehrnhoefer DE, Wobst H, Neugebauer K, Wanker, EE (2010). EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc Natl Acad Sci USA 107(17): 7710-5. http://www.ncbi.nlm.nih.gov/pubmed/20385841

6 Fassler M, Zocher M, Klare S, de la Fuente AG, Scheuermann J, Capell A, Haass C, Valkova C, Veerappan A, Schneider D, Kaether C (2010). Masking of transmembrane-based retention signals controls ER export of gamma-secretase. Traffic. 11(2):250-8. http://www.ncbi.nlm.nih.gov/pubmed/19958468

7 Mi W, Pawlik M, Sastre M, Jung SS, Radvinsky DS, Klein AM, Sommer J, Schmidt SD, Nixon RA, Mathews PM, Levy E (2007). Cystatin C inhibits amyloid-beta deposition in Alzheimer's disease mouse models. Nat Genet. 39:1440-1442. http://www.ncbi.nlm.nih.gov/pubmed/18026100

8 Maetzler W, Stoycheva V, Schmid B, Schulte C, Hauser AK, Brockmann K, Melms A, Gasser T, Berg D. Neprilysin Activity in Cerebrospinal Fluid is Associated with Dementia and Amyloid-β42 Levels in Lewy Body Disease. J Alzheimers Dis. Epub ahead of print. http://www.ncbi.nlm.nih.gov/pubmed/20858953

9 Lutz AK, N Exner, M. E. Fett, J. S. Schlehe, K. Kloos, K. Lammermann, B. Brunner, A. Kurz-Drexler, F. Vogel, A. S. Reichert, L. Bouman, D. Vogt-Weisenhorn, W. Wurst, J. Tatzelt, C. Haass, and K. F. Winklhofer. 2009. Loss of Parkin or PINK1 Function Increases Drp1-dependent Mitochondrial Fragmentation. The Journal of biological chemistry 284:22938-22951. http://www.ncbi.nlm.nih.gov/pubmed/19546216

10 Irrcher I, Aleyasin H, Seifert EL, Hewitt SJ, Chhabra S, Phillips M, Lutz, AK, Rousseaux MW, Bevilacqua L, Jahani-Asl A, Callaghan S, Maclaurin JG, Winklhofer KF, Rizzu P, Rippstein P, Kim RH, Chen CX, Fon EA, Slack RS, Harper ME, McBride HM, Mak TW, Park DS (2010). Loss of the Parkinson's disease-linked gene DJ-1 perturbs mitochondrial dynamics. Hum Mol Genet, 19, 3734-3746.
http://www.ncbi.nlm.nih.gov/pubmed/20639397

11 Kamp F, Exner N, Lutz AK, Wender N, Hegermann J, Brunner B, Nuscher B, Bartels T, Giese A, Beyer K, Eimer S, Winklhofer KF, Haass C (2010). Inhibition of Mitochondrial Fusion by a-Synuclein is rescued by PINK1, Parkin, and DJ-1. EMBO J, 29, 3571-3589. http://www.ncbi.nlm.nih.gov/pubmed/20842103

12 Meixner, A., Boldt K., Van Troys M, Askenazi M., Gloeckner C.J., Bauer M., Marto J.A., Ampe C., Kinkl N., Ueffing M. (2010) A QUICK screen for Lrrk2 interaction partners leucine-rich repeat kinase 2 is involved in actin cytoskeleton dynamics. Mol Cell Proteomics. Epub ahead of print.
http://www.ncbi.nlm.nih.gov/pubmed/20876399

13 Fiesel FC, Voigt A, Weber SS, Van den Haute C, Waldenmaier A, Görner K, Walter M, Anderson ML, Kern JV, Rasse TM, Schmidt T, Springer W, Kirchner R, Bonin M, Neumann M, Baekelandt V, Alunni-Fabbroni M, Schulz JB, Kahle PJ (2010). Knockdown of transactive response DNA-binding protein TDP-43 downregulates histone deacetylase 6. EMBO J. 29, 209-221. http://www.ncbi.nlm.nih.gov/pubmed/19910924

14 Ehm O, Göritz C, Covic M, Schäffner I, Schwarz TJ, Karaca E, Kempkes B, Kremmer E, Pfrieger FW, Espinosa L, Bigas A, Giachino C, Taylor V, Frisén J, Lie DC (2010). RBPJkappa-dependent signaling is essential for long-term maintenance of neural stem cells in the adult hippocampus. J Neurosci. 30(41):13794-807. http://www.ncbi.nlm.nih.gov/pubmed/20943920

15 Jawerka M, Colak D, Dimou L, Spiller C, Lagger S, Montgomery RL, Olson EN, Wurst W, Göttlicher M, Götz M (2010). The specific role of histone deacetylase 2 in adult neurogenesis. Neuron Glia Biology 6, 93-107. http://www.ncbi.nlm.nih.gov/pubmed/20388229

16 Ninkovic J., Pinto L., Petricca S., Sun J., Rieger M.A., Schroeder T., Cvekl A., Favor J. and Götz M. (2010). The transcription factor Pax6 regulates survival of dopaminergic olfactory bulb neurons via crystallin alphaA. Neuron, in press. http://www.ncbi.nlm.nih.gov/pubmed/21092858

17 Heinrich C, Blum R, Tripathi P, Götz M, Berninger B (2010a). Directing astroglia from the cerebral cortex into functional subtype-specific neurons. PLOS Biology 8. Epub ahead of print.
http://www.ncbi.nlm.nih.gov/pubmed/20502524

18 Heinrich C, Gascón S, Masserdotti G, Lepier A, Sanchez R, Simon-Ebert T, Schroeder T, Götz M, Berninger B (2010b). Generation of subtype specific neurons from postnatal astroglia of the mouse cerebral cortex. Nature Protocols, in press.

19 Bouman L, Schlierf A, Lutz AK, Shan J, Deinlein A, Kast J, Galehdar Z, Palmisano V, Patenge N, Berg D, Gasser T, Augustin R, Trümbach D, Irrcher I, Park D, Wurst W, Kilberg MS, Tatzelt J, Winklhofer KF (2010). Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. Cell Death Differ. Epub ahead of print. http://www.ncbi.nlm.nih.gov/pubmed/21113145

20 Tsolakidou A., Czibere L., Pütz B., Trümbach D., Panhuysen M., Deussing J. M., Wurst W., Sillaber I., Landgraf R., Holsboer F., and T. Rein. 2010. Gene expression profiling in the stress control brain region hypothalamic paraventricular nucleus reveals a novel gene network including amyloid beta precursor protein. BMC Genomics 11(1): 546. http://www.ncbi.nlm.nih.gov/pubmed/20932279