Neurodegenerative Disorders Flashcards
review of protein folding
*newly synthesized proteins folded in ER
-chaperoned by heat-shock proteins
-aid in proper folding, assist in transport (ER, golgi, mitochondria, etc)
ER stress: unfolded protein cell response
*cell tries to restore protein homeostasis
*detection of excess abnormally folded proteins leads to:
-decreased protein synthesis
-concurrent increase in chaperone proteins
*if response inadequate (ER stress) -> actively signals apoptosis
ER stress
*protein folding DEMAND > protein folding CAPACITY
*leads to failure of adaptation and subsequent apoptosis
proteinopathies
*progressive damage to neuronal groups due to accumulation of abnormal protein
*classifications:
1. symptomatic/anatomic classification (specific anatomical regional signs/symptoms)
2. pathological classification (based on protein/inclusion structures)
neurodegeneration of cerebral cortex & hippocampus
*Alzheimer disease
*cognitive changes that progress to dementia
neurodegeneration of basal ganglia
*Parkinson, Huntington
*movement disorders, hypokinetic or hyperkinetic
neurodegeneration of cerebellum
*spinocerebellar ataxias
*disorders of balance (ataxia)
neurodegeneration of spinal cord motor systems
*ALS
*limb weakness and difficulty with swallowing and breathing
pathogenesis of neurodegenerative diseases
- proteins from insoluble aggregates/inclusions
-mutations -> protein prone to aggregation and resistant to proteolysis
-protein clearance defects -> gradual accumulation of proteins - small aggregates are neurotoxic
-trigger unfolded protein response -> apoptotic cell death
-lead to loss of function of protein
-may impair gene transcription or protein synthesis
*large aggregates are visible as inclusion bodies
-aberrant localization/sequestration within neurons
-morphologic diagnostic hallmarks
Alzheimer disease - overview
*degenerative disease of cortex
*accumulation of β-amyloid (Aβ) and tau protein in specific brain regions
Alzheimer disease - early onset familial genetics
mutations in APP cleavage enzymes; presenilin 1/2 genes
Alzheimer disease - late onset familial genetics
apoplipoprotein E (ApoE allele epsilon 4) strong influence increased risk
Alzheimer disease & Down syndrome
*increased risk/occurrence with Down syndrome
*extra copy of APP on chromosome 21
Alzheimer disease - pathogenesis
*accumulation of β-amyloid (Aβ) and tau protein in specific brain regions
*PLAQUES AND NEUROFIBRILLARY TANGLES
Alzheimer disease - pathogenesis of PLAQUES
*EXTRAcellular aggregated β-amyloid peptides
*APP cleavage -> extracellular β-amyloid oligomer fibrils
*disrupt synapses, elicits microglia/astrocyte response
*may form around vessels, leading to increased parenchymal hemorrhage
Alzheimer disease - pathogenesis of NEUROFIBRILLARY TANGLES
*INTRAcellular aggregates of microtubule binding protein tau
*hyperphosphorylation leads to intracellular aggregates and dystrophic neurites
*disrupt microtubule function
*elicit stress response -> apoptotic neuronal death
Alzheimer disease - epidemiology
*most common cause of dementia in older adults
*incidence increases with age (AGE IS THE MOST IMPORTANT RISK FACTOR)
*prevalence doubles every 5 years
*25% genetic predisposition: early onset familial form vs. late-onset familial form; increased risk w/ Down syndrome
Alzheimer disease - clinical features
*memory loss; impaired higher intellectual function
*altered mood and behavior
*apraxia (loss of previously learned motor tasks, such as dressing or using eating utensils)
*agnosia (poor processing of sensory info, such as inability to recognize faces or voices as familiar)
*over time, disorientation & aphasia develop
*final phases are profoundly disabled, often mute, and immobile
Alzheimer disease - plaques (simplified)
*extracellular
*β-amyloid aggregates
Alzheimer disease - tangles (simplified)
*intracellular
*tau aggregates
Alzheimer disease - common causes of death
*usually pneumonia or other infections
Alzheimer disease - pathologic findings
*diffuse cortical atrophy (narrowing of gyri, widening of sulci, dilation of ventricles hydrocephalus ex vacuo)
*neuritic plaques (extracellular β-amyloid aggregates)
*neurofibrillary tangles (intracellular tau aggregates)
frontotemporal lobar degeneration (FTLD) - overview
disorders associated with focal degeneration of frontal and/or temporal lobes
frontotemporal lobar degeneration (FTLD) - etiology
*heritable and sporadic variants
1. FTLD tau variants: mutations in MAPT (tau gene)
2. FTLD-TDP variants: hexanucleotide repeats of C9orf72 (most common) - same as ALS
frontotemporal lobar degeneration (FTLD) - clinical manifestation
*adult-onset progressive neurodegenerative syndromes
*related to site of neuronal loss:
-frontal lobe = behavior disturbances, cognitive impairment
-temporal lobe = language difficulties
*global dementia may occur with progressive disease
*note - there can be overlap between ALS and FTLD
frontotemporal lobar degeneration (FTLD) - pathology
*atrophy and neuronal loss and gliosis of frontal/temporal lobes; aggregation of either of the following:
1. TDP-43 protein = characteristic needle-like inclusions
2. tau protein = neurofibrillary tangles
*ABSENT β-amyloid deposits
FTLD: Pick’s Disease
*subtype of FTLD-tau
*severe asymmetric frontotemporal atrophy (reducing gyri to wafer-thin or knife-efge appearance; sparing of posterior 2/3 of superior temporal gyrus)
*neuronal loss and gliosis (surviving neurons show swelling Pick bodies = Tau+ round intracytoplasmic inclusions)
*behavioral and language symptoms arise early
Parkinson disease - overview
*degenerative disease caused by loss of dopaminergic neurons from the substantia nigra
Parkinson disease - etiology
*common disorder of aging (2% of adults)
*most cases sporadic; rare familial forms
Parkinson disease - pathogenesis
*α-synuclein aggregates (Lewy Bodies)
*neurons damaged by loss of protein function or toxic accumulated misfolded proteins
*degeneration of dopaminergic neurons of substantia nigra
Parkinson disease - clinical features
*triad:
1. tremor - “pill-rolling,” resting
2. rigidity - causing postural instability and gait difficulties
3. bradykinesia - gradual and progressive slowing of movement
*absence of toxic or other known underlying etiology
*dementia in late stages
*confirmed by symptomatic response to L-DOPA replacement therapy
Parkinson disease - pathologic findings
*pallor of substantia nigra and locus ceruleus (loss of pigmented neurons)
*Lewy bodies - composed of α-synuclein; predominantly found in dopaminergic neurons of substantia nigra
*Lewy neurites
*areas of neuronal show gliosis
Huntington disease - overview
movement disorder caused by degeneration of the caudate and putamen GABAergic neurons
Huntington disease - etiology
*autosomal dominant: expanded CAG repeats in HTT gene (4p16.3)
*paternal transmission anticipation: further expansions of repeats occur during spermatogenesis (associated with earlier onset of disease in next generation)
*NO sporadic form known
Huntington disease - pathogenesis
*increased glutamine-encoding CAG trinucleotide repeats in Huntingtin gene
*toxic gain-of-function protein with poorly defined mechanisms of neuronal injury
*mutant protein undergoes proteolysis to generate fragments that form intranuclear ubiquinated aggregates
Huntington disease - clinical features
*chorea (involuntary, jerky, writhing movements) of all parts of body
*early cognitive sx: forgetfulness and thought & affective disorders
*late cognitive sx: progression to severe dementia
*relentlessly progressive
Huntington disease - pathologic findings
*dramatic atrophy of caudate & putamen nuclei (symmetric lateral ventricular dilation, loss of GABA neurons, gliosis)
*intranuclear inclusions of ubiquitinated HTT protein
amyotrophic lateral sclerosis (ALS) - overview
*degeneration of motor neurons in the spinal cord, brainstem, and motor cortex, resulting in muscle weakness and spasticity
*upper motor neuron loss in cerebral cortex AND lower motor neuron loss in anterior horns of spinal cord
amyotrophic lateral sclerosis (ALS) - etiology
*90% of cases are sporadic
*familial forms - autosomal dominant (C9orf72 or SOD-1)
amyotrophic lateral sclerosis (ALS) - clinical features
*UMN loss: spasticity, abnormally brisk deep tendon reflexes, Babinski sign
*LMN loss: asymmetric weakness, fasciculations, atrophy in muscles, brainstem dysfunction, respiratory failure
*eventually involves respiratory muscles, leading to death from respiratory failure/pneumonia
*NO sensory loss
*note - there can be overlap between ALS and FTLD
amyotrophic lateral sclerosis (ALS) - pathologic findings
*intranuclear inclusions:
-Bunina bodies (rope-like inclusions)
-TDP-43 inclusions
*degeneration of motor neurons and reactive gliosis (loss of neurons in spinal cord anterior horns; spinal cord atrophy, loss of myelinated fibers)
*atrophic skeletal muscles
spinocerebellar ataxias - overview
*trinucleotide repeat expansions in various genes leading to neuronal degeneration in different regions of the brain
*heterogenous, typically autosomal dominant disorders
*polyglutamine expansions (CAG) affecting different proteins
*typically present in middle age
Friedrich ataxia - etiology
*autosomal recessive
*GAA repeat expansions, frataxin gene
Friedrich ataxia - pathology
*mitochondrial dysfunction with increased oxidative damage
*involvement of spinocerebellar tract, corticospinal tract, and posterior columns
Friedrich ataxia - clinical features
*gait ataxia
*sensory peripheral neuropathy
*weakness
*spasticity
*hypertrophic cardiomyopathy
*diabetes
*sclerosis
Prion diseases - overview
*rapidly progressive neurodegenerative disorders caused by aggregation and intercellular spread of misfolded Prion Protein (PrP)
prion disease - pathogenesis
*normal PrPc undergoes protease-resistant misfolding, forming PrPSC (may be spontaneous or genetic)
*abnormally folded PrPSC induces conformational changes in other, normal PrPc, accumulating in neural tissue and causing progressive neural damage
prion disease - pathologic findings
*spongiform encephalopathy (vacuolated neurons; brain tissue neuropil has sponge-like appearance)
*Kuru plaques = aggregates of PrPSC
Creutzfeldt-Jakob disease
*most common prion disease
*presents as rapidly progressive dementia
*associated with pronounced startle myoclonus
*uniformly fatal
*3 etiologic forms:
-sporadic (majority of cases)
-inherited (mutations in PRNP)
-acquired (iatrogenic transmission)
Alzheimer disease - region mainly affected
cerebral cortex, hippocampus
Alzheimer disease - protein aggregates
*β-amyloid (Aβ) plaques (extracellular)
*tau tangles (intracellular)
Alzheimer disease - neurologic deficits (simplified)
dementia
frontotemporal lobar degeneration (FTLD) - region mainly affected
frontal and temporal lobes
frontotemporal lobar degeneration (FTLD) - protein aggregates
*Tau (pick bodies)
OR
*TDP-43 inclusions
frontotemporal lobar degeneration (FTLD) - neurologic deficits (simplified)
behavioral changes; dementia
Parkinson disease - region mainly affected
substantia nigra
Parkinson disease - protein aggregates
α-synuclein
Parkinson disease - neurologic deficits (simplified)
hypokinetic movement disorder; dementia (late)
Huntington disease - region mainly affected
caudate nucleus > putamen > cortex
Huntington disease - protein aggregates
Huntingtin intranuclear inclusions
Huntington disease - neurologic deficits (simplified)
hyperkinetic movement (chorea); dementia
spinocerebellar ataxias - region mainly affected
cerebellar cortex, spinal cord, and other regions
spinocerebellar ataxias - protein aggregates
*various proteins with intranuclear inclusions
spinocerebellar ataxias - neurologic deficits (simplified)
ataxia (balance disorder)
amyotrophic lateral sclerosis - region mainly affected
anterior roots of spinal cord
amyotrophic lateral sclerosis - protein aggregates
*Bunina bodies
*SOD-1
*TDP-43
amyotrophic lateral sclerosis - neurologic deficits (simplified)
*progressive weakness and paralysis
*UMN and LMN sx
*NO sensory loss
prion diseases - region mainly affected
cerebral cortex
prion diseases - protein aggregates
PrP (kuru plaques)
prion diseases - neurologic deficits (simplified)
rapidly progressive dementia
