Clinical Neuroscience - ALS

Wichtige Krankheitsbilder der Neurowissenschaften

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Flashcards	18
Language	English
Category	Medical
Level	University
Created / Updated	24.05.2014 / 31.05.2015
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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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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

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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

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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

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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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

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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

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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

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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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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

What is the clinical overlap between ALS and FTLD?

15% of patients in FTLD develop motor neuron symptoms

20% of patients in ALS develop FTLD disease

15% of patients in ALS develop FTLD disease

20% of patients in FTLD develop motor neuron symptoms

Difference: ALS: progressive paralysis & FTLD: behavioral dysfunction

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15% of patients in FTLD develop motor neuron symptoms

20% of patients in ALS develop FTLD disease

15% of patients in ALS develop FTLD disease

20% of patients in FTLD develop motor neuron symptoms

Difference: ALS: progressive paralysis & FTLD: behavioral dysfunction

The hard facts about FTLD - frontotemporal lobar degeneration - are?

Incidence: 5-15:100.000, life expectansy: 2-10 years

FTLD is also a progressive and adult onset disease

manifested in ubiquitin protein inclusions in frontal lobe

major symptoms: behavior changes, language dysfunction, emotional coldness and apathy

FTLD is not a brain disease

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Incidence: 5-15:100.000, life expectansy: 2-10 years

FTLD is also a progressive and adult onset disease

manifested in ubiquitin protein inclusions in frontal lobe

major symptoms: behavior changes, language dysfunction, emotional coldness and apathy

FTLD is not a brain disease

What is true about sporadic ALS?

major protein component of inclusions is TDP43

TDP43 can be ubiquinated

TDP43 can be phosphorylated

TDP43 can be terminal fragmented

TDP43 inclusions are not shared between sALS and FTLD

major protein component of inclusions is TDP43

TDP43 can be ubiquinated

TDP43 can be phosphorylated

TDP43 can be terminal fragmented

TDP43 inclusions are not shared between sALS and FTLD

What is true about familiar ALS?

20% of all cases are caused by mutation in SOD1 gene

stable dimer of SOD1 is disrupted

ubiquitin inclusions with SOD1

inclusions are controverse in in sALS

dense inclusions visible

20% of all cases are caused by mutation in SOD1 gene

stable dimer of SOD1 is disrupted

ubiquitin inclusions with SOD1

inclusions are controverse in in sALS

dense inclusions visible

What is true about the distribution of ALS?

90% = sporadic (sALS)

sALS is mostly idiopathic but 10% have a genetic cause (fALS)

10% = familiar (fALS)

causes for fALS among sALS are de novo mutation and incomplete patient history

80% = sporadic (sALS)

90% = sporadic (sALS)

sALS is mostly idiopathic but 10% have a genetic cause (fALS)

10% = familiar (fALS)

causes for fALS among sALS are de novo mutation and incomplete patient history

80% = sporadic (sALS)

Hard facts of ALS - Amyotrophe Lateralsclerosis - are? (ALS is also called Charcot's or Lou Gehrig's disease.)

progressive and adult onset

incidence 1:100.000, life expectancy after onset: 1-5 years

upper/lower motor neuron degeneration

is not manifested with ubiquitin protein inclusions in spinal cord

Major Symptoms: muscle weakness --> paralysis --> respiratory failure

progressive and adult onset

incidence 1:100.000, life expectancy after onset: 1-5 years

upper/lower motor neuron degeneration

is not manifested with ubiquitin protein inclusions in spinal cord

Major Symptoms: muscle weakness --> paralysis --> respiratory failure

What anatomical parts of the body are affected with ALS?

Upper motor neurons

UMNs are located in the lateral corticospinal tract

Lower motor neurons

LWM are located in the anterior horn cells

muscle

Upper motor neurons

UMNs are located in the lateral corticospinal tract

Lower motor neurons

LWM are located in the anterior horn cells

muscle

What are the hallmarks (Kennzeichen) of ALS progression?

central: denervation and atrophy of muscle (loss of spinal motor neurons)

process usually begins focally: 2/3 starts spinal (leg or arm)

process usually begins focally: 1/3 starts bulbar (swalloing or speech difficulties)

positive symptoms: cramps

no positive symptoms: fasciculations (muscle twitches)

central: denervation and atrophy of muscle (loss of spinal motor neurons)

process usually begins focally: 2/3 starts spinal (leg or arm)

process usually begins focally: 1/3 starts bulbar (swalloing or speech difficulties)

positive symptoms: cramps

no positive symptoms: fasciculations (muscle twitches)

What is correct about the DIAGNOSIS of ALS?

there are no biological markers konwn yet

diagnosis relies on history, clinical and neurophysiological findings

exception: known mutations in fALS

Onset: at the point of clinical presentation ~50% of MNs are lost

there is no diagnostic delay (misdiagnosis ~45%)

there are no biological markers konwn yet

diagnosis relies on history, clinical and neurophysiological findings

exception: known mutations in fALS

Onset: at the point of clinical presentation ~50% of MNs are lost

there is no diagnostic delay (misdiagnosis ~45%)

ALS is a aggressive disease. After 10 years only 10% of all patients are alive. What is true about the treatment of ALS?

overall goal: obtain highest score in quality of life

palliative treatment with opoids

medication: riluzole (neuroprotective mode?) shows inhibition of glutamate release in rats

medication: THC (showed delayed progression in SOD1)

it is possible to treat more than the present symptoms of muscle atrophy

overall goal: obtain highest score in quality of life

palliative treatment with opoids

medication: riluzole (neuroprotective mode?) shows inhibition of glutamate release in rats

medication: THC (showed delayed progression in SOD1)

it is possible to treat more than the present symptoms of muscle atrophy

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