5/27- Degenerative Disorders Flashcards
Symptoms seen with loss of cortical neurons?
Dementia
Symptoms seen with loss of basal ganglia neurons?
Movement disorder
Symptoms seen with loss of cerebellar neurons?
Ataxia
Symptoms seen with loss of motor neurons?
Weakness
What causes neuronal death in degeneration?
Diverse insults
Common final pathways (work in concert):
- Excitotoxicity
- Free radical injury
- Protein fibrillogenesis (extra/intracellular)
(Death via either necrosis or apoptosis)
Consequences of neuronal death (broad, 2)
- System dysfunction
- NT loss
What does it mean if cellular reaction to injury is “reactive”?
It can recover (Necrosis-Apoptosis-Reactive-Normal)
What is protein fibrillogenesis?
Protein misfolds and starts to polymerize/accumulate, aggregating into fibrils or filaments which may lead to cellular dysfunction or death
(early phases e.g. fibrils rather than inclusions are more destructive)
Types of protein fibrillogenesis?
May be:
- Extracellular protein deposit, “plaque”
- Intracellular protein deposit, “inclusion” (most intra are cytoplasmic, but some nuclear) (Innocent bystander proteins may be incorporated into fibrillization/inclusions)
How can fibrillogenesis be identified?
- Light or electron microscopy
- Immunohistochemistry for inclusions in nucleus/cytoplasm
What is the “stress protein”? What does it do?
Ubiquitin
Marks the misfolded protein for refolding or degradation by proteasome
What is a non-proteasome pathway for degradation of misfolded protein?
Autophagy by lysosomes
Composition of cytoplasmic inclusions?
Structural protein:
- Tau
- Synuclein
Stress protein:
- Ubiquitin
- Crystalline
- HSPs
Difference between structure and toxicity of fibrils vs. inclusions?
Fibrils: ultrastructural, nm, VERY toxic
Inclusions: light microscopy, um, less toxic
What is Tau protein? Causes what diseases?
Intracellular neuronal protein associated with microtubules
Causes “Tauopathies”
What is alpha-synuclein? Causes what diseases?
Intracellular neuronal and glial protein
Causes Lewy body disorders, e.g. Parkinson’s
What is superoxide dismutase (SOD)? Causes what diseases?
Intracellular neuronal protein
Causes Familial ALS (can oxidize just fine, but protein misfolds and causes problems)
What is beta-amyloid? Causes what diseases?
Extracellular polymeration
Causes Alzheimer’s Disease
T/F: Neuodegeneration is focal/localized? 3 examples?
False
Neurodegeneration may start focally and then spread
- Alzheimer’s typ starts in hippocampus with memory problems (but may start in Broca’s area with progressive aphasia)
- Parkinson’s may start in 1 substantia nigra; hemikparkinsonism
- ALS may start focally (e.g. hand weakness on 1 side); as dz progresses, it spreads to other muscle groups
Three main steps in prion-like templating of neurodegeneration?
- Misfolding (stochastic, failure to degrade, or genetic propensity to misfold)
- Templating (misfolded pr modifies 2’ structure of native protein in self-replicating cycle)
- Aggregation (misfolded prot tends to aggregate; IC = tangles)
Examples of overlapping neurodegenerative diseases (2)
- Parkinson’s: dementia following movement disorder
- ALS: later frontotemporal dementia
What is a prion?
Misfolded protein that is so capable of modifying 2’ structure of native protein in self-replicating cycle that it is INFECTIOUS
What is this?
Cortical atrophy (caudate atrophy)
Can see hydrocephalus ex vacuo
What is this?
Cortical atrophy: atrophic frontal/temporal lobes moreso than parietal/occipital
Which side is abnormal?
In what way?
Disease?
Abnormal: right side
Problem: substantia nigra atrophy
Disease: Parkinson’s disease
What are these histo pics of?
Which is abnormal?
Disease?
Pictures of substantia nigra
Abnormal: right side
Problem: Parkinson’s disease
What is shown in this picture?
Lewy body in pigmented neuron in Parkinson’s disease
What is the composition of Lewy bodies?
Extra or intracellular?
- Intracellular (cytoplasmic)
Strucutral protein: synuclein
Stress protein:
- Ubiquitin
- Crystalline
- HSPs
What is shown in this picutre?
Cortical Lew bodies (a-Synuclein)
Most common causes of dementia (due to cortical degeneration)?
- Alzheimer’s
- Pick’s disease (frontotemporal dementia)
- Lewy body dementia (person with Parkinson’s can develop this or vice versa, this can lead into Parkinson’s)
Important pic
KNOW THIS
Symptoms of Parkinson’s disease (7)
- Cogwheel rigidity
- Resting tremor
- Bradykinesis
- Postural instability
- Clasp knife tonicity ?
(-masked facies)
(-en bloc turning)
Non a-synuclein misfolding (Lewy body formation) causes of Parkinsonism?
- Post-encephalitic Parkinsonism
- Progressive supranuclear palsy (tauopathy)
What is this? (pic 8)
Progressive supranuclear palsy (PSP)
What is this?
Tau immunoreactive Globose Nueronal tangle in PSP (progressive supranuclear palsy)
What is multiple system atrophy (MSA)?
Degenerative dz with varying components of parkinsonism, cerebellar ataxia, and autonomic dysfunction once thought to be 3 separate diseases It is a synucleinopathy (a-synuclein); glial cytoplasmic inclusions, GCI
What is underlying mechanism of the different symptoms seen in MSA (multiple system atrophy)?
- Parkinsonism: striatonigral degeneration
- Ataxia: olivopontocerebellar degeneration
- Autonomic dysfct: Shy Drager dysautonomia
What degenerates in MSA?
- Substantia nigra
- Putamen
- Olivary nuclei
- Pontine nuclei
- Cerebellum
What does this show?
Atrophy of pons in multiple system atrophy
What does this show?
Alpha-synuclein positive inclusions in multiple system atrophy
What is Friedreich’s ataxia?
What protein does it involve?
Most common hereditary ataxia
- Autosomal recessive
- GAA triplet repeat expansion (both alleles or one with expansion and other with mutation)
- Involves frataxin but NOT appeared to be a fibrillogenesis-related dz
- Results in loss of function
What organs does Friedreich’s ataxia affect?
- CNS
- Heart
- Pancreas
What does this show?
Cerebellar atrophy seen in Friedreich’s ataxia and other spinocerebellar ataxias
What does this show?
Friedreich’s ataxia Multiple long tracts affected, including psinocerebellar
What does this show?
Amyotrophic lateral sclerosis (ALS)
What parts of the SC are affected in ALS (tracts)?
- Corticospinal tract (lateral and anterior/ventral)
- Ventral horns
What does this show?
Amyotrophic Lateral Sclerosis (ALS)
What causes ALS?
Familial forms from SOD1 (superoxide dismutase) mutations
Protein fibrils formal and damage cells (not a loss of free radical handling! Still functional)
Forms amyloid-like filaments and water-filled nanotubes
