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18 Multiple Choice Antworten
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
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
Pathogenic mechanims of C9ORF72 expansions is?
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
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
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
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
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
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
