Exam 2 NEU 534

Direct Pathway

“go pathway”

decreases basal ganglia inhibition of thalamus

allows movement

Indirect Pathway

“no go pathway”

increases basal ganglia inhibition of thalamus

blocks movement

D1 receptors

excitatory dopamine recepto

couples with Gs protein to activate adenylate cyclase, increasing cAMP

D2 receptors

inhibitory dopamine receptor

couples with Gi protein to inhibit adenylate cyclase, reducing cAMP

Tyrosine hydroxylase (TH)

converts tyrosine into levodopa (L-DOPA)

L-amino acid decarboxylase (LAADC)

Converts levodopa (L-DOPA) into dopamine

Levodopa (L-DOPA)

Precursor to dopamine

F-DOPA

when used in PET scans of Parkinson’s patients, less uptake = damage to dopaminergic neurons

Primary motor symptoms of parkinson’s

tremor at rest, bradykinesia, rigidity

Bradykinesia

slowness of movement

Inputs to basal ganglia are x, outputs from BG are y

excitatory/glutamatergic, inhibitory/GABAergic

Lewey bodies

found in Parkinson’s and other diseases, contain alpha-synuclein

present in both sporadic and familial Parkinson’s

may play a cytoprotective role

Motor symptoms in Parkinson’s appear after what?

80-90% of substantia nigra par compacta neurons are lost

Prodromal symptom of Parkinson’s

constipation

not diagnostic, often appears in patient history years before diagnosis

SNCA

Genetic risk factor for Parkinson’s

Autosomal dominant

Encodes alpha-synuclein

Aggresomes

segregate and facilitate degradation of damaged/mutated/misfolded proteins

SNc dopamine neurons are particularly vulnerable due to

metabolic stress and oxidative stress

Causes of metabolic stress in SNc

energetically expensive dendritic arbors and long, unmyelinated axons

autonomic pacemaker activity

Causes of oxidative stress in SNc

High levels of dopamine and its metabolites, which produce ROS

Increased oxidative stress combined with mitochondrial dysfunction → impairment of lysosomal autophagy system

Lysosomal autophagy system (LAS)

Involved in removal of alpha-synuclein

MPTP

contaminant of MPPP (synthetic opioid)

causes symptoms of parkinson’s

selective inhibitor of ETC complex 1

Rotenone

Herbicide

Linked to parkinson’s

ETC complex 1 inhibitor

Oxidative stress

Production of reactive oxygen species (ROS) outweighs removal by antioxidant enzymes

Superoxide dismutase

an antioxidant enzyme

can turn superoxide radical into hydrogen peroxide

Most common oxygen free radicals

hydroxyl radical and superoxide radical

hydrogen peroxide

not a free radical, but reactions can lead to production of free radicals

Catalase

Converts hydrogen peroxide into water and oxygen

Dopamine-o-quinone

Oxidized from dopamine

Reactive intermediate

Can be turned into 6-hydroxydopamine

6-hydroxydopamine

Damaging compound that is derived from dopamine-o-quinone, a reactive intermediate of dopamine

Generates significant superoxide radical by inhibiting ETC complex 1

Neuromelanin

gives SNc its pigmentation

sequesters toxic byproducts of dopamine metabolism

alterations contribute to processes that lead to PD

ETC and ROS

inevitable electron leakage during oxidative phosphorylation

ETC complexes 1 & 3 → diffusion into mitochondrial matrix and intermembrane space

generate superoxide radical

Factors that can contribute to electron leakage

Advancing age, environmental toxins (MPTP, rotenone), or misfolded proteins (alpha-synuclein)

cytochrome c

pro-apoptotic factor

mice injected with alpha-synuclein had less what?

tyrosine hydroxylase positive neurons in the substantia nigra

N-terminal region of alpha-synuclein

Several familial Parkinson’s mutations (A53T, E46K, and A30P) found in this location

Central region of alpha-synuclein

High tendencies to produce beta-pleated sheets that are prone to aggregation

C-terminal region of alpha-synuclein

rich in proline and negatively charged residues (common characteristic of intrinsically disordered proteins)

Alpha-synuclein represents what % of the total protein population?

1

Under physiological conditions, alpha synuclein exists in what state?

Soluble random coil state

What prevents misfolding of alpha-synuclein?

chaperones, proteasomes, phagosome/lysosome systems

What aspect of the aging brain contributes to the accumulation of misfolded alpha synuclein?

A progressive decline in proteolytic defense mechanisms

Amyloid fibrils

Neuronal death in parkinson’s disease

1. excess oxidative stress

2. misfolding of alpha-synuclein

3. misfolded alpha-synuclein is degraded by proteosomes

4. misfolded alpha-synuclein is sequestered into Lewey bodies

5. misfolded alpha-synuclein increases ROS production in mitochondria

6. mitochondria become dysfunctional, cant produce ATP

7. impaired ATP and increase in ROS leads to toxicity and death

8. Other contributing factors include dopamine oxidation

What happens to normal fetal cells transplanted into the SN of Parkinson’s patients?

they develop Lewey bodies

Misfolded alpha-synuclein can do what to normal alpha-synuclein?

seed

Cell-to-cell spread

misfolded alpha-synuclein can spread between neurons

Alpha-synuclein oligomers can cross what?

the blood-brain barrier

Braak hypothesis

possible mechanism for spread of misfolded alpha-synuclein from gut to brain

Carbidopa

Prevents levodopa from being converted into dopamine in the PNS

Deep brain stimulation

changes firing rate and pattern of individual neurons in the basal ganglia

promotes release of local neurotransmitters

increases blood flow

stimulates neurogenesis

Potential mechanism of DBS

may reduce hypersynchronized circuits

DBS electrodes record what?

local field potentials

Beta-sheet rich secondary structure

shared by all disease causing proteins

cross beta structure

beta sheets are perpendicular to the long axis of the fiber

amyloidgenesis

Conversion from normal alpha-helical rich conformation to pathological beta-sheet rich

Tau and amyloid beta

implicated in Alzheimer’s

Prion proteins

implicated in CJD, mad cow disease, kuru, chronic wasting disease, scrapie

Prion

proteinaceous infectious particle

proteins that acquire alternative conformations that become self propagating

Protein only hypothesis

prions are misfolded proteins that are infectious in the absence of nucleic acids

PRNP gene

encodes cellular prion protein

mutations implicated in familial Creutzfeldt-Jakob disease

Transmissible Spongiform Encephalopathies

Accumulation of prion protein causes translational repression of global protein synthesis that leads to neuronal death

Mechanism of neuronal death in Transmissible Spongiform Encephalopathies

may involve oxidative stress and excitotoxicity

Sporadic Creutzfeldt-Jakob disease

no mutations in PRNP gene

New cases of sCJD annually

1 million world wide, 350 in the united states

Median survival time after onset of CJD symptoms

4 months

Deletion of PRNP in mice

Leads to immunity to prion disease

Inheritance of fCJD

autosomal dominant

Iatrogenic

disease caused by medical intervention

Cadaveric human growth hormone

used to treat children with short stature from the 50s through 1985

contamination with prions led to CJD in some patients

some patients also developed amyloid-beta deposits

mice expressing human amyloid beta injected with contaminated chGH

developed amyloid beta plaques

vCJD

occurs when prions from cows with bovine spongiform encephalopathy spreads to human

231 cases reported as of 2018

PrP Sc

disease causing form of prion protein

has different biochemical properties than PrP c - for instance, it is protease resistant

Prion disease species barrier

four residues in protein are implicated - Asn108, Met112, Met129, and Ala13

PrP c

“normal” form of prion protein

glycosylphosphatidylinositol-anchored plasma membrane glycoprotein

may function within lipid rafts to regulate various signal
transduction pathways

Small oligomeric assemblies of PrP Sc

Thought to be primary causative agent of prion disease pathology

protein folding “fast track”

alpha and beta domains fold concurrently and form intermediate conformation

protein folding “slow track”

chain becomes trapped in long-lived intermediate with persistent structure only in the alpha domain

further folding requires transition over high energy barrier or partial unfolding

unfolded state of protein

has high conformational entropy

nucleation is [ ] for most proteins in physiological settings

extremely unlikely

lag phase

prion monomers self-assemble into amyloid fibers after this

it is eliminated by addition of preformed prion oligomer seeds

primordial polypeptide conformation

may be represented by beta-sheet-rich amyloid fibers

self replicating protein conformations in early life forms

amyloid conformations of fibrin-derived peptides

activate tissue type plasminogen activator

Sup35

yeast protein that regulates translation

propogates as a prion

Hsp104

hexameric yeast protein that
has two ATPase domains

Low concentrations of Hsp104

promotes Sup35 fiber assembly in two ways

• binds ATP, Hsp104 catalyzes the formation of amyloidogenic Sup35 oligomers, eliminates lag

• couples ATP hydrolysis to the severing of a small subset of short Sup35 fibers, which generates extra surfaces for conformational replication, accelerates fiber assembly

High concentrations

couples ATPase activity to the disassembly of amyloidogenic oligomers and fibers of Sup35

might minimize the half-life of amyloidogenic structures

promotes cell survival after exposure to environmental stress

Aplaysia CPEB (ApCPEB)

regulates translation of mRNA
shown to have prion like properties

participate in maintenance of long-term potentiation

ApCPEB and long term potentiation

Sensory transduction

detection of stimulus energy and translation into electrical signal

Amplitude coding

size of electrical response in sensory receptor cell increases with strength of stimulus

receptor potentials (type of graded potential)

Frequency coding

stimulus intensity is coded by frequency of action potentials

Sensory adaptation

response of receptor cell diminishes or disappears in response to sustained stimulus

Sensory receptors respond best to what?

Changes in stimuli

Receptive field

Sub-region of a sensory surface to which an individual sensory receptor cell responses

Four types of somatic sensation

1. Touch – mechanotransduction
2. Proprioception – mechanotransduction
3. Temperature – thermotransduction
4. Nociception – multimodal: mechano-, thermo- & chemotransduction

Receptive fields in hands are?

smaller

Two-point discrimination

the ability to discern two closely spaced stimuli

Lateral inhibition

carried out by lateral inhibitory neurons at the second-order level

allows for two-point discrimination when receptive fields overlap

The difference between the directly stimulated regions on the skin and the immediately adjacent
neighboring areas is larger in the secondary neurons than in the primary sensory neurons themselves

Pacinian corpuscles

large receptive fields

very sensitive to vibration

respond best to stimulus onset and offset

Meissner’s corpuscles

small receptive fields

very sensitive to vibration

respond best to stimulus onset and offset