pedigree als85 m m m m w w w w m m w w w w w familial als m377v sporadic als g294a sporadic als...
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Pedigree ALS85
MM
MM
W WW W
MM W W WW W
Familial ALSM377V
Sporadic ALS G294A
Sporadic ALS Q331K
RNA binding proteins and neurodegeneration: TDP 43
Sreedharan et al. Science 2008
Wild type M337V
Chick embryo
Developmentaldelay
TransverseSection
IHC
Transgene expression
TunelStaining
ApoptoticCells
FTD ALS/MND
Average age at onset 35 yearsAverage survival 12 monthsLinkage to Chromosome 16LOD score = 4Ruddy et al. AJHG 2003
RNA binding proteins and neurodegeneration: FUS
Arg 515 Gly Arg 521 His Arg 521 Cys
3 different missense mutations8 unrelated familial ALS kindreds
FUS R514G
Wildtype
FUS
GFP-FUSAnti-FUS DAPI Merge
Mutations cause FUS to relocate to the cytoplasmBecause they disrupt their nuclear localising signal
Mutant FUS forms cytoplasmic inclusions In ALS patients
Vance et al . Science 2009
Toxic RNA expansion and neurodegeneration: ORF72
= ALS = FTD = ALS-FTD
Multigenerational Dutch kindredALS and FTD variable phenotypeLinkage to Chr 9p LOD score = 3
Vance et al. Brain 2006
Le Ber et.al 2009Gijselinck 2010
Momeni et.al 2006Morita et.al 2006
Vance et.al 2006
Valdmanis et.al 2007
Pearson 2011Boxer et.al 2010
~ 4MB Overlap
10 kindreds linkedRegion narrowed to 4MBBAC haploid clonesDNA captureBrain RNA sequencedWhole genomeNext generation seq.97 SNP common haplotype
C9ORF72 intronic hexanucleotide (GGGGCC)nexpansion mutation700 to 1,000 repeatsDe Jesus-Hernandez Neuron 2011Renton et al Neuron 2011
Expanded Intronic repeat detected by PCR and Southern Blot