Editorial | Open | Published:
Molecular neurodegeneration: basic biology and disease pathways
Molecular Neurodegenerationvolume 9, Article number: 34 (2014)
The field of neurodegeneration research has been advancing rapidly over the past few years, and has provided intriguing new insights into the normal physiological functions and pathogenic roles of a wide range of molecules associated with several devastating neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington’s disease, and Down syndrome. Recent developments have also facilitated initial efforts to translate preclinical discoveries toward novel therapeutic approaches and clinical trials in humans. These recent developments are reviewed in the current Review Series on "Molecular Neurodegeneration : Basic Biology and Disease Pathways" in a number of state-of-the-art manuscripts that cover themes presented at the Third International Conference on Molecular Neurodegeneration: "Basic biology and disease pathways" held in Cannes, France, September, 2013.
In September 2013, the Third International Conference on Molecular Neurodegeneration: "Basic biology and disease pathways" was held in Cannes, France. The three-day conference brought together scientists from around the world to present and discuss the results of their most recent research on the normal physiological functions and pathological mechanisms of molecular pathways that are relevant to neurodegenerative diseases (Figure 1). The current thematic review series in the journal, entitled "Molecular Neurodegeneration : Basic Biology and Disease Pathways", is intended to represent not only the scientific findings presented during the conference, but to also reflect the state-of-the-art in a given field. The review series will consist of a "rolling submission" format in which manuscripts by presenters at the conference will appear at regular intervals in the journal.
The conference covered a wide array of topics concerning neurodegeneration at the genetic, molecular, cellular, physiological, behavioral, and systems levels, and with a translational perspective of moving discoveries from preclinical models into human clinical trials. Sessions discussed the following areas of neurodegeneration research:
The genetics of AD and other neurodegenerative diseases
The structure and normal physiological functions of molecules involved in neurodegeneration
Novel molecular mechanisms of AD, PD, ALS, FTD, DS, and HD
Mechanisms of neurotoxicity in PD, AD and other tauopathies
Novel therapeutic approaches for neurodegenerative diseases
Molecular mechanisms of neurodegeneration were dominant themes of the conference. Some highlights included novel insights into AD pathogenesis provided by genetic analyses revealing new AD risk factor genes like CD33 and TREM2 involved in innate immunity [1–4]. Deeper knowledge of the structures and normal physiological functions of APP and the α-, β- and γ-secretase enzymes that process APP is assisting the development of disease-modifying AD therapies that target the neurotoxic Aβ peptide [5–9]. Intriguing studies have revealed new molecules involved in neurodegeneration, like C9ORF72 in ALS and FTD, and begin to shed light on their pathogenic roles [10–12]. New insights into the prion-like spread of Aβ and tau pathologies in AD and α-synuclein in PD have also been made [13–15]. Additionally, innovative studies of mechanisms of neurotoxicity have revealed roles for micro-RNAs, transcription factors, and trafficking molecules in AD [16–20]. Novel therapies based on many of these discoveries are also in development, like anti-tau antibodies for AD and other tauopathies .
In summary, this review series aims to encapsulate the themes discussed at the Third International Conference on Molecular Neurodegeneration and provide state-of-the-art knowledge of a wide range of fields in neurodegeneration research. It is the hope of the editors that the knowledge conveyed in the review series will provide quality information to readers and stimulate further scientific advances in molecular neurodegeneration that may someday bring an end to these devastating neurodegenerative disorders.
Amyotrophic lateral sclerosis
Amyloid precursor protein
Chromosome 9 open reading frame 72
Cluster of differentiation 33
Triggering receptor expressed on myeloid cells 2.
Tanzi RE: The genetics of Alzheimer disease. Cold Spring Harbor Perspect Med. 2012, 2 (10): Epub 2012/10/03. doi:10.1101/cshperspect.a006296. PubMed PMID: 23028126
Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, Hooli B, Choi SH, Hyman BT, Tanzi RE: Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron. 2013, 78 (4): 631-43. 10.1016/j.neuron.2013.04.014. doi:10.1016/j.neuron.2013.04.014, PubMed PMID: 23623698, PubMed Central PMCID: PMC3706457
Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J: Alzheimer Genetic Analysis G. TREM2 variants in Alzheimer's disease. N Engl J Med. 2013, 368 (2): 117-27. 10.1056/NEJMoa1211851.
Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD, Jarvik GP, Crane PK, Larson EB, Bird TD, Boeve BF, Graff-Radford NR, De Jager PL, Evans D, Schneider JA, Carrasquillo MM, Ertekin-Taner N, Younkin SG, Cruchaga C, Kauwe JS, Nowotny P, Kramer P, Hardy J, Huentelman MJ, Myers AJ, Barmada MM, Demirci FY, Baldwin CT, et al: Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet. 2011, 43 (5): 436-41. 10.1038/ng.801. Epub 2011/04/05. doi:10.1038/ng.801. PubMed PMID: 21460841.
Muller UC, Zheng H: Physiological functions of APP family proteins. Cold Spring Harbor Perspect Med. 2012, 2 (2): a006288-doi:10.1101/cshperspect.a006288, PubMed PMID: 22355794, PubMed Central PMCID: PMC3281588
Renzi F, Zhang X, Rice WJ, Torres-Arancivia C, Gomez-Llorente Y, Diaz R, Ahn K, Yu C, Li YM, Sisodia SS, Ubarretxena-Belandia I: Structure of gamma-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy. J Biol Chem. 2011, 286 (24): 21440-9. 10.1074/jbc.M110.193326. doi:10.1074/jbc.M110.193326, PubMed PMID: 21454611, PubMed Central PMCID: PMC3122203
Vassar R, Kuhn PH, Haass C, Kennedy ME, Rajendran L, Wong PC, Lichtenthaler SF: Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects. J Neurochem. 2014, doi:10.1111/jnc.12715. PubMed PMID: 24646365
Chami L, Checler F: BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and beta-amyloid production in Alzheimer's disease. Mol Neurodegener. 2012, 7: 52-10.1186/1750-1326-7-52. doi:10.1186/1750-1326-7-52, PubMed PMID: 23039869, PubMed Central PMCID: PMC3507664
Walter J, van Echten-Deckert G: Cross-talk of membrane lipids and Alzheimer-related proteins. Mol Neurodegener. 2013, 8: 34-10.1186/1750-1326-8-34. doi:10.1186/1750-1326-8-34, PubMed PMID: 24148205, PubMed Central PMCID: PMC4016522
Meyer K, Ferraiuolo L, Miranda CJ, Likhite S, McElroy S, Renusch S, Ditsworth D, Lagier-Tourenne C, Smith RA, Ravits J, Burghes AH, Shaw PJ, Cleveland DW, Kolb SJ, Kaspar BK: Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc Natl Acad Sci U S A. 2014, 111 (2): 829-32. 10.1073/pnas.1314085111. doi:10.1073/pnas.1314085111, PubMed PMID: 24379375; PubMed Central PMCID: PMC3896192
Ling SC, Polymenidou M, Cleveland DW: Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron. 2013, 79 (3): 416-38. 10.1016/j.neuron.2013.07.033. doi:10.1016/j.neuron.2013.07.033, PubMed PMID: 23931993
Xu ZS: Does a loss of TDP-43 function cause neurodegeneration?. Mol Neurodegener. 2012, 7: 27-10.1186/1750-1326-7-27. doi:10.1186/1750-1326-7-27, PubMed PMID: 22697423, PubMed Central PMCID: PMC3419078
Jucker M, Walker LC: Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 2013, 501 (7465): 45-51. 10.1038/nature12481. 10.1038/nature12481, PubMed PMID: 24005412, PubMed Central PMCID: PMC3963807
Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM: Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron. 2013, 80 (2): 402-14. 10.1016/j.neuron.2013.07.046. 10.1016/j.neuron.2013.07.046, PubMed PMID: 24075978; PubMed Central PMCID: PMC3924573
Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B, Riddle DM, Kwong LK, Xu Y, Trojanowski JQ, Lee VM: Distinct alpha-synuclein strains differentially promote tau inclusions in neurons. Cell. 2013, 154 (1): 103-17. 10.1016/j.cell.2013.05.057. doi:10.1016/j.cell.2013.05.057, PubMed PMID: 23827677; PubMed Central PMCID: PMC3820001
Lau P, Bossers K, Janky R, Salta E, Frigerio CS, Barbash S, Rothman R, Sierksma AS, Thathiah A, Greenberg D, Papadopoulou AS, Achsel T, Ayoubi T, Soreq H, Verhaagen J, Swaab DF, Aerts S, De Strooper B: Alteration of the microRNA network during the progression of Alzheimer's disease. EMBO Mol Med. 2013, 5 (10): 1613-34. 10.1002/emmm.201201974. doi:10.1002/emmm.201201974, PubMed PMID: 24014289, PubMed Central PMCID: PMC3799583
Duplan E, Giaime E, Viotti J, Sevalle J, Corti O, Brice A, Ariga H, Qi L, Checler F, da Alves Costa C: ER-stress-associated functional link between Parkin and DJ-1 via a transcriptional cascade involving the tumor suppressor p53 and the spliced X-box binding protein XBP-1. J Cell Sci. 2013, 126 (Pt 9): 2124-33.
Wang X, Zhao Y, Zhang X, Badie H, Zhou Y, Mu Y, Loo LS, Cai L, Thompson RC, Yang B, Chen Y, Johnson PF, Wu C, Bu G, Mobley WC, Zhang D, Gage FH, Ranscht B, Zhang YW, Lipton SA, Hong W, Xu H: Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome. Nat Med. 2013, 19 (4): 473-80. 10.1038/nm.3117. doi:10.1038/nm.3117, PubMed PMID: 23524343; PubMed Central PMCID: PMC3911880
Buggia-Prevot V, Fernandez CG, Riordan S, Vetrivel KS, Roseman J, Waters J, Bindokas VP, Vassar R, Thinakaran G: Axonal BACE1 dynamics and targeting in hippocampal neurons: a role for Rab11 GTPase. Mol Neurodegener. 2014, 9 (1): 1-10.1186/1750-1326-9-1. doi:10.1186/1750-1326-9-1, PubMed PMID: 24386896; PubMed Central PMCID: PMC4031619
Buggia-Prevot V, Fernandez CG, Udayar V, Vetrivel KS, Elie A, Roseman J, Sasse VA, Lefkow M, Meckler X, Bhattacharyya S, George M, Kar S, Bindokas VP, Parent AT, Rajendran L, Band H, Vassar R, Thinakaran G: A function for EHD family proteins in unidirectional retrograde dendritic transport of BACE1 and Alzheimer's disease Abeta production. Cell Rep. 2013, 5 (6): 1552-63. 10.1016/j.celrep.2013.12.006. doi:10.1016/j.celrep.2013.12.006, PubMed PMID: 24373286; PubMed Central PMCID: PMC3932704
We thank the editors of Molecular Neurodegeneration for the invitation for this review series, and particularly the authors of the review manuscripts for their efforts. We further want to express our thanks to all the speakers and participants of the Third International Conference on Molecular Neurodegeneration, who are too numerous to mention by name.