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RNA binding proteins and neurodegeneration: TDP 43. Familial ALS M377V. Chick embryo. Developmental delay. W. W. W. M. W. M. Pedigree ALS85. Transverse Section IHC. Transgene expression. W. W. W. W. W. M. M. M. M. Apoptotic Cells. Tunel Staining.

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Presentation Transcript
slide1

RNA binding proteins and neurodegeneration: TDP 43

Familial ALS

M377V

Chick

embryo

Developmental

delay

W

W

W

M

W

M

Pedigree ALS85

Transverse

Section

IHC

Transgene

expression

W

W

W

W

W

M

M

M

M

Apoptotic

Cells

Tunel

Staining

Wild type M337V

FTD

ALS/MND

Sporadic ALS G294A

Sporadic ALS Q331K

Sreedharan et al. Science 2008

slide2

RNA binding proteins and neurodegeneration: FUS

Anti-FUS

GFP-FUS

DAPI

Merge

Wildtype

FUS

FUS R514G

Average age at onset 35 years

Average survival 12 months

Linkage to Chromosome 16

LOD score = 4

Ruddy et al. AJHG 2003

3 different missense mutations

8 unrelated familial ALS kindreds

Arg 521 Cys

Arg 515 Gly

Arg 521 His

Mutant FUS forms cytoplasmic inclusions In ALS patients

Mutations cause FUS to relocate to the cytoplasm

Because they disrupt their nuclear localising signal

Vance et al . Science 2009

slide3

Toxic RNA expansion and neurodegeneration: ORF72

Le Ber et.al 2009

Gijselinck 2010

Momeni et.al 2006

Morita et.al 2006

Vance et.al 2006

Valdmanis et.al 2007

Pearson 2011

Boxer et.al 2010

~ 4MB Overlap

= ALS-FTD

= ALS

= FTD

Multigenerational Dutch kindred

ALS and FTD variable phenotype

Linkage to Chr 9p

LOD score = 3

Vance et al. Brain 2006

10 kindreds linked

Region narrowed to 4MB

BAC haploid clones

DNA capture

Brain RNA sequenced

Whole genome

Next generation seq.

97 SNP common haplotype

C9ORF72 intronic

hexanucleotide (GGGGCC)n

expansion mutation

700 to 1,000 repeats

De Jesus-Hernandez Neuron 2011

Renton et al Neuron 2011

Expanded Intronic repeat detected by PCR and Southern Blot