(Read Only) Rouleau_US Neurology 16/02/2010 10:15 Page 38
Neurodegenerative Disease Amyotrophic Lateral Sclerosis
significance of disease-causing TDP-43 mutations in ALS pathogenesis phosphorylated TDP-43 and its export from the nucleus plays, and
is essential and timely. Furthermore, relevant to motor neurons and whether it has a role in motor neuron demise, are not well understood.
ALS, TDP-43 has previously been shown to interact with the survival
motor neuron (SMN) protein
35
and contribute to the alternative splicing Finally, in a mechanism that would draw parallels with SOD1, TDP-43
of SMN2 exon seven.
36
This has interesting correlations since copy mutations could yield an as-yet unknown toxic gain of function that
number variants of the SMN1 and SMN2 genes have been suggested as is selectively vulnerable to motor neurons, thus leading to their
susceptibility factors for the development of ALS.
37
Finally, TDP-43 has demise in ALS patients. Using in vivo and in vitro models, our group
been demonstrated to be localized in the neuronal RNA granules and to and collaborators in the ALS field are currently exploring these
play a role in dendrite maintenance in motor neurons.
38
Also, TDP-43 possibilities in order to understand the functional significance of TDP-
has been shown to have a nuclear localization signal and to be mainly 43 mutations in ALS pathogenesis. These models will be a great tool
localized in the nucleus.
39
It is possible that TDP-43 mutations may to further our knowledge of ALS pathophysiology. Most importantly,
disrupt the nuclear signal and its transport to the cytosol, where TDP-43 pharmacological treatments that prolong disease duration and onset
may be more likely to be aggregated. TDP-43 has also been shown to be in mut SOD1 transgenic mice can be tested also using these mut TDP-
cleaved by caspases and thus could represent a marker of disease 43 animal models prior to entering the very labor-intensive and
pathology and apoptotic processes.
40
However, the function that expensive road of human clinical trials. n
1. Andersen PM, Amyotrophic lateral sclerosis associated with 15. Mackenzie IR, Bigio EH, Ince PG, et al., Pathological TDP-43 common cause of sporadic amyotrophic lateral sclerosis,
mutations in the CuZn superoxide dismutase gene, Curr distinguishes sporadic amyotrophic lateral sclerosis from PLoS ONE, 2008;3:e2450.
Neurol Neurosci Rep, 2006;6:37–46. amyotrophic lateral sclerosis with SOD1 mutations, Ann 29. Buratti E, Brindisi A, Giombi M, et al., TDP-43 binds
2. Hudson AJ, Amyotrophic lateral sclerosis and its association Neurol, 2007;61:427–34. heterogeneous nuclear ribonucleoprotein A/B through its
with dementia, parkinsonism and other neurological 16. Cairns NJ, Neumann M, Bigio EH, et al., TDP-43 in familial C-terminal tail: an important region for the inhibition of
disorders: a review, Brain, 1981;104:217–47. and sporadic frontotemporal lobar degeneration with cystic fibrosis transmembrane conductance regulator exon
3. Rosen DR, Siddique T, Patterson D, et al., Mutations in Cu/Zn ubiquitin inclusions, Am J Pathol, 2007;171:227–40. 9 splicing, J Biol Chem, 2005;280:37572–84.
superoxide dismutase gene are associated with familial 17. Fujita Y, Mizuno Y, Takatama M, Okamoto K, Anterior horn 30. Buratti E, Baralle FE, Multiple roles of TDP-43 in gene
amyotrophic lateral sclerosis, Nature, 1993;362:59–62. cells with abnormal TDP-43 immunoreactivities show expression, splicing regulation, and human disease,
4. Cudkowicz ME, McKenna-Yasek D, Sapp PE, et al., fragmentation of the Golgi apparatus in ALS, J Neurol Sci, Front Biosci, 2008;13:867–78.
Epidemiology of mutations in superoxide dismutase in 2008;269:30–34. 31. Winton MJ, Igaz LM, Wong MM, et al., Disturbance of
amyotrophic lateral sclerosis, Ann Neurol, 1997;41:210–21. 18. Cairns NJ, Bigio EH, Mackenzie IR, et al., Neuropathologic nuclear and cytoplasmic TAR DNA binding protein (TDP-43)
5. Borchelt DR, Lee MK, Slunt HS, et al., Superoxide dismutase diagnostic and nosologic criteria for frontotemporal lobar induces disease-like redistribution, sequestration and
1 with mutations linked to familial amyotrophic lateral degeneration: consensus of the Consortium for aggregate formation, J Biol Chem, 2008;283:13302–9.
sclerosis possesses significant activity, Proc Natl Acad Sci Frontotemporal Lobar Degeneration, Acta Neuropathol, 32. Ou SH, Wu F, Harrich D, et al., Cloning and characterization
U S A, 1994;91:8292–6. 2007;114:5–22. of a novel cellular protein, TDP-43, that binds to human
6. Reaume AG, Elliott JL, Hoffman EK, et al., Motor neurons in 19. Kabashi E, Valdmanis PN, Dion P, et al., TARDBP mutations immunodeficiency virus type 1 TAR DNA sequence motifs,
Cu/Zn superoxide dismutase-deficient mice develop in individuals with sporadic and familial amyotrophic lateral J Virol, 1995;69:3584–96.
normally but exhibit enhanced cell death after axonal injury, sclerosis, Nat Genet, 2008;40:572–4. 33. Ayala YM, Pantano S, D’Ambrogio A, et al., Human,
Nat Genet, 1996;13:43–7. 20. Rutherford NJ, Zhang YJ, Baker M, et al., Novel mutations in Drosophila, and C.elegans TDP43: nucleic acid binding
7. Gurney ME, Pu H, Chiu AY, et al., Motor neuron TARDBP (TDP-43) in patients with familial amyotrophic properties and splicing regulatory function, J Mol Biol,
degeneration in mice that express a human Cu,Zn lateral sclerosis, PLoS Genet, 2008;4:e1000193. 2005;348:575–88.
superoxide dismutase mutation, Science, 1994;264:1772–5. 21. Sreedharan J, Blair IP, Tripathi VB, et al., TDP-43 mutations 34. Forman MS, Trojanowski JQ, Lee VM, TDP-43: a novel
8. Boillee S, Vande Velde C, Cleveland DW, ALS: a disease of in familial and sporadic amyotrophic lateral sclerosis, neurodegenerative proteinopathy, Curr Opin Neurobiol,
motor neurons and their nonneuronal neighbors, Neuron, Science, 2008;319:1668–72. 2007;17:548–55.
2006;52:39–59. 22. Van Deerlin VM, Leverenz JB, Bekris LM, et al., TARDBP 35. Wang IF, Reddy NM, Shen CK, Higher order arrangement
9. Clement AM, Nguyen MD, Roberts EA, et al., Wild-type mutations in amyotrophic lateral sclerosis with TDP-43 of the eukaryotic nuclear bodies, Proc Natl Acad Sci U S A,
nonneuronal cells extend survival of SOD1 mutant motor neuropathology: a genetic and histopathological analysis, 2002;99:13583–8.
neurons in ALS mice, Science, 2003;302:113–17. Lancet Neurol, 2008;7:409–16. 36. Kashima T, Rao N, David CJ, Manley JL, hnRNP A1 functions
10. Hutton M, Lendon CL, Rizzu P, et al., Association of 23. Yokoseki A, Shiga A, Tan CF, et al., TDP-43 mutation in with specificity in repression of SMN2 exon 7 splicing, Hum
missense and 5´-splice-site mutations in tau with the familial amyotrophic lateral sclerosis, Ann Neurol, 2008;63: Mol Genet, 2007;16:3149–59.
inherited dementia FTDP-17, Nature, 1998;393:702–5. 538–42. 37. Veldink JH, Kalmijn S, Van der Hout AH, et al., SMN
11. Neumann M, Sampathu DM, Kwong LK, et al., Ubiquitinated 24. Gitcho MA, Baloh RH, Chakraverty S, et al., TDP-43 A315T genotypes producing less SMN protein increase
TDP-43 in frontotemporal lobar degeneration and mutation in familial motor neuron disease, Ann Neurol, susceptibility to and severity of sporadic ALS, Neurology,
amyotrophic lateral sclerosis, Science, 2006;314:130–33. 2008;63:535–8. 2005;65:820–25.
12. Arai T, Hasegawa M, Akiyama H, et al., TDP-43 is a 25. Kuhnlein P, Sperfeld AD, Vanmassenhove B, et al., Two 38. Wang IF, Wu LS, Chang HY, Shen CK, TDP-43, the signature
component of ubiquitin-positive tau-negative inclusions in German kindreds with familial amyotrophic lateral sclerosis protein of FTLD-U, is a neuronal activity-responsive factor,
frontotemporal lobar degeneration and amyotrophic lateral due to TARDBP mutations, Arch Neurol, 2008;65:1185–9. J Neurochem, 2008;105:797–806.
sclerosis, Biochem Biophys Res Commun, 2006;351:602–11. 26. Daoud H, Valdmanis PN, Kabashi E, et al., Contribution of 39. Winton MJ, Igaz LM, Wong MM, et al., Disturbance of
13. Hasegawa M, Arai T, Nonaka T, et al., Phosphorylated TDP- TARDBP mutations to sporadic amyotrophic lateral nuclear and cytoplasmic TAR DNA-binding protein (TDP-43)
43 in frontotemporal lobar degeneration and amyotrophic sclerosis, J Med Genet, 2009;46:112–14. induces disease-like redistribution, sequestration, and
lateral sclerosis, Ann Neurol, 2008;64:60–70. 27. Gijselinck I, Sleegers K, Engelborghs S, et al., Neuronal aggregate formation, J Biol Chem, 2008;283:13302–9.
14. Strong MJ, Volkening K, Hammond R, et al., TDP43 is a inclusion protein TDP-43 has no primary genetic role in FTD 40. Zhang YJ, Xu YF, Dickey CA, et al., Progranulin mediates
human low molecular weight neurofilament (hNFL) mRNA- and ALS, Neurobiol Aging, 2009;30:1329–31. caspase-dependent cleavage of TAR DNA binding protein-
binding protein, Mol Cell Neurosci, 2007;35:320–27. 28. Guerreiro RJ, Schymick JC, Crews C, et al., TDP-43 is not a 43, J Neurosci, 2007;27:10530–34.
38 US NEUROLOGY
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100