Neurodegenerative Disorders

Question 1

Neurodegenerative disorders

Answer 1

Heterogeneous group of disorders that are characterized by the progressive degeneration of the structure and function of CNS or PNS

Question 2

Aging

Answer 2

-main risk factor for modt neurodegenerative diseases
-hallmarks of aging correlate with susceptibility to neurodegenerative disorders

Question 3

Selective vulnerability

Answer 3

Clinical manifestations reflect distinct and overlapping neuronal circuits that progressively degenerate in various neurodegenerative disorders

Question 4

Pathological hallmarks

Answer 4

-accumulation of characteristic proteins into insoluble aggregates within and/or between neurons, along with cell dysfunction and neuronal death

Question 5

Common pathways altered in neurodegenerative diseases

Answer 5

-protein quality control
-autophagy—lysome pathway
-mitochondria homeostasis
-protein seeding and propagation
-synaptic toxicity and network dysfunction
-calcium homeostasis

Question 6

Parkinson’s disease

Answer 6

Progressive degeneration of dopaminergic neurons

Question 7

Pathological hallmarks in Parkinson’s

Answer 7

-a-synuclein protejn as main component of lewg bodies and lewy neurites, the defining feature of PD
-neurons degenerate in the substantia nigra of the midbrain and their projection terminals in the striatum

Question 8

Payhophysiology of a-synuclein

Answer 8

-unfolded monomers interact to form initially unstable dimers
-grow slowly to generate oligomers of varying morphologies
-transient spherical and ring-like oligomers that eventually convert to fibrils
-accumulation of oligomers, protofibrils and fibrils, that can not be degraded contribute to a-synuclein-mediated toxicity
-reducing a-syn expression, aggregation, or propagation, or increasing the clearance of this protein all suggest viable therapeutic strategies for combating Parkinson’s disease and related disorders

Question 9

Dopamine synthesis and degradation pathwags in PD treatment

Answer 9

-tyrosine -> L-Dopa -> dopamine
-Levodopa is most effectjve antiparkinsonian ned, provides relatively rapid symptomatic benefits, all PD patients generally require LDopa therapy

Question 10

Levodopa has narrow therapeutic window for Parkinson’s disease

Answer 10

-after five hears, nearly 50% develop motor complications and after ten years 100% are affected
-dystonia: painful, prolonged muscle contractions cause abnormal movements and postures
-dyskinesia: involuntary, erratic, writhing movements of the face, arms, legs, or trunk

Question 11

Alzheimers (healthy)

Answer 11

-entorhinal cortex -> hippocampus
-affected regions shrink as nerve cells die

Question 12

Alzheimers (mild)

Answer 12

-AD spreads through brain, cerebral cortex begins to shrink as more and more neurons stop working and die
-mild AD signs can include memory loss, confusion, trouble handling money, poor judgment, mood changes, and increased anxiety
-moderate AD signs can inclhde increased memory loss and confusion, problems recognizing people, difficulty with language and thoughts, restlessness, agitation, wandering, and repetitive statements

Question 13

Alzheimers (advanced)

Answer 13

-In severe AD, extreme dhrinkage occurs
-weight loss, seizures, skin infections, groaning, moaning, or grunting. Increased sleeping, loss of bladder and bowel control
-death from aspiration pneumonia or other infections

Question 14

Tole of APP and beta amyloid

Answer 14

-APP thought to contribute to synaptic formation and plasticity
-when cleaved by a-secretase in middle of beta amyloid domain, it is not amyloifogenic
-APP is cleaved by beta and y secrete enzymes, neurotoxic Abeta peptides are released, which can accumulate into oligomer aggregate
-app cleavage produces soluble Abeta that js secreted into extracellular space
-mutations in APP gene tend to inhibit cleavage by a-sec and consequently enable prefrential cleavage by beta-src
-mutations jn the presenilin-1 and presenilin-2 genes increase cleavage by y-src at this site

Question 15

B-amyloif mechanisms of action

Answer 15

-soluble AB can binf to other molecules of AB to form oligomers that are cleared more slowy from the brain or which can accrete to form insoluble AB plaques
-insoluble B-sheet amyloidfibrils thought to trigger local inflammatory response
Amyloif proteins lead to formation of neurofibrilatory tangles, and both produce AD symtpoms

Question 16

Tau Protein function

Answer 16

Normally bind and stablize microtubules
-Tau protein binds to tubulin molecules to facilitate assembly if tublin into microtubules. And, in combination with other microtubule associated proteins, tau protein maintains the stability of microtubules

Question 17

Phosphorylatrr Tau anf Neurofibrillary Tangles

Answer 17

-NFT are msde from HP-tau
-HP-tau reduces the bunding of tau to microtubules
-HP-tau does not bind to tubulin but attached to other MAPs and acts as an aggregate center
-reduces the amount of tau available to bind microtubules
-HP-tau molecules block the formation of microtubules and undermind stability of existing microtubules
-prevent axonal transport and synaptic loss