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Hard facts II about ALS?

life time risk: females 1:8000 / males 1:600

disease peaks around age of 60

sporadic or familial ALS --> no genes are known

Incidence: 2:100.000

Prevalence: 5-9:100.000

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TDP43/FUS aggregation might be based on the model of proteinopathies meaning that protein aggregation leads to disease onset.

TDP43/FUS stress granules might be the first step in aggregation

Proteinopathie: false folded protein (prion) binds/unfolds normal proteins

prion unfolding triggers loss of function by proteasomal degradation

aggregation results in plaque formation

TDP43/FUS inclusions located in spinal cord

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Pathogenic mechanims of C9ORF72 expansions is?

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Haploinsuffiency = reduced levels of transcripts

RNA-mediated toxicity

RNA-mediated toxicity includes sequestration

RNA-mediated toxicity includes RNA-binding protein in RNA foci

Dipeptide protein toxicity = formation of toxic aggregates

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Which are common targets of TDP43 and FUS?

generell: targets are a set of ~45 RNA

long-intron containing transcripts

multiple intronic binding sites for TDP43/FUS

downregulated upon loss in TDP43/FUS

reduced in motor neurons with TDP43 inclusions

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What is true about TDP43?

essential protein: transport of RNA containing granules (axon transport to distal site)

required for early development of inner cell mass

autoregulation of protein level by binding own mRNA (non-sense mediated decay)

TDP43 toxicity: may be mediated by loss of function, gain of toxic funtion or both

experimental approach: high throughput sequencing

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Animal models are used in ALS: what is true?

models of transgenic mice and rats

overexpression of SOD1 & ALS linked mutation replicates human disease

overexpression of TDP43 or FUS withe ALS linked mutation does not recapitulate diesease

overexpression of SOD1 & ALS linked mutation does not replicate human disease

overexpression of TDP43 or FUS withe ALS linked mutation recapitulates human disease

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Pathological Overlap of ALS and FTLD?

TDP43 aggregation and mislocalization

TDP43 is a RNA/DNA-binding protein

>35 mutations of low complexity domain change conformational state

5% ALS: globular state changed to aggregated

10% ALS: globular state changed to aggregated

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Genetic overlap of ALS and FTDL?

Homozygous SNP: TMEM106B protects from FTLD

Ataxin-2: Poly-Q-repeat expansion is a risk factor for ALS

Genetic cause of ALS/FTLD: Hexanucleotide expansion of C9ORF72 is most common

normal repeat length = 2-26 G4C2 and pathological repeat length = 700-4400 G4C2

typical: TDP43-inclusions, dipetide aggregates and repeat RNA foci