Rehahi litacija - Letnik V 11. 111f1/ . -1 ( 2008/
TDP-43 IN SPORADIC ANO FAMILIAL 
ALS 
B. Rogelj, J. Sreedharan, C. Vance, V. Tripathi, S. Ackerley, T. Horto
�
agy, C. E. Sh
_
aw
MRC Centre far Neurodegeneration Research, Department of Cl1nical Neurosc1ence, Institute of
Psychiatry, King's College London, London, UK 
For nearly 20 years the neuropathological hallmark of 
ALS has been polyubiquitinated skein-like and globu­
lar inclusions in the perikaryon and proximal axon of 
motor neurons in the brain stem and spina] cord. These 
have recently been shown to colocalise with a 25kDa, 
C-terminal, detergent-resistant f
r
agment of TAR DNA 
binding protein TDP-43. These inclusions are present 
in -90% of ALS cases and a subset of frontotemporal 
]obar degeneration cases now termed the "TDP-43 pro­
tein opathies" ( 1-3). TDP-43 is predominantly a nuclear 
protein but in those neurons with the most 
�
tri
�
ing cyto­
plasmic inclusions there is a marked reduct1on 111 n
�
1clear
TDP-43, suggesting that it has been sequestered 111 the 
cytoplasm and that miss-localisation may play a role in 
pathogenesis. 
We have recently identified a TARDBP mutation (the 
gene encoding TDP-43) in a single familial ALS kindred 
(4). The mutation is predicted to result in a single amino­
acid substitution of methionine for vali ne at rcsidue 337. 
We also identified two sporadic MND missense mutations 
(Q331 K and G293A) in neighbouring amino acids . The 
onl y two mutations studied showed increased tendency to 
protein cleavage and were toxic to the embryonic chick 
spina! cord neurons causing apoptosis and developmental 
delay. 
Fourteen missense mutations have now been reported in 
familial and sporadic MND (3, 5-7). Ali but one of the 
mutations. reside in the C-terminal domain. 
The findi no of rare mutations in TARDBP in familial and 
b 
sporadic ALS does implicate a mechanistic role for TDP-43 
clea vage, mislocalisation and aggregation in ALS and FfD. 
These pathogenic mutations should provide important bio­
logical tools that will enable us to develop more informativc 
cellular and animal models of ALS. 
References: 
l. Neumann M, Sampathu DM, Kwong LK, Truax AC,
Micsenyi MC, Chou TI, et al. Ubiquitinated TDP-43
in frontotemporal !obar degeneration and amyotrophic
lateral sclerosis. Science 2006; 314 (5796): 130-3.
2. Arai T, Hasegawa M, Akiyama H, lkeda K, Nonaka T,
Mori H, et al „ TDP-43 is a component of ubiquitin­
positive tau-negative inclusions in frontotempornl !obar
degener ntion and amyotrophic laterni sclerosis. Biochem
Biophys Res Commun 2006: 351 (3): 602- 1 1.
3. Gitcho MA, Baloh RH, Chakrnverty S, Mayo K, Norton
JB, Levitch D, ct al. TDP-43 A315T mutation in familial
motor neuron clisease. Ann Neurol 2008; 63 (4): 535-8.
4. Sreeclharan J, Blair IP, Tripathi YB, Hu X, Yance C,
Rogelj B, et al. TDP-43 mutations in familial and sporadic
amyotrophic lateral sclerosis. Science 2008; 319 (5870):
1668-72.
5. Van Deerlin YM , Leverenz JB, Bekris LM, Bird TD,
Yuan W, Elman LB, et al. TARDBP mutations in amyo­
trophic laterni sclerosis with TDP-43 neuropathology:
a genetic and histopathological anal ysis. Lancet Neurol
2008; 7 (5): 409-16.
6. Kwong LK, Neumann M, Sampathu DM. Lee YM. Tro­
janowski JQ. TDP-43 proteinopathy: The neuropatho logy
underlying major forms of sporadic and familial f
r
onto­
tcmporal !obar degencration and motor neuron diseasc.
Acta Ncuropathol 2007; 11 4 ( 1 ): 63-70.
7. Yokoseki A. Shiga A, Tan CF, Tagawa A. Kaneko H.
Koyama A, et al. TDP-43 mutation in familial amyotroph­
ic laterni sclerosis. Ann Neurol 2008: 63 ( 4 ): 538-42.
ii