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Clinical Neuroscience - ALS

Wichtige Krankheitsbilder der Neurowissenschaften

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Kartei Details

Karten	18
Sprache	English
Kategorie	Medizin
Stufe	Universität
Erstellt / Aktualisiert	24.05.2014 / 31.05.2015
Lizenzierung	Keine Angabe
Weblink	https://card2brain.ch/box/clinical_neuroscience_als
Einbinden	<iframe src="https://card2brain.ch/box/clinical_neuroscience_als/embed" width="780" height="150" scrolling="no" frameborder="0"></iframe>

Flip-Modus

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

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