FINAL EXAM Flashcards
Lectures 7 and on
MANGANESE (Mn)
- Naturally occuring elelment in the Earth’s crust found at low levels in ________, ______, _______, and _________
- Essential element of the human _______
- Is a _________ for enzymes like glutamine synthetase, arginase, pyruvate carboxylase, etc
- Helps to regulate __________, energy _______________, _________ function, _____________ defenses, ___________ and _______________
water, air, soil, food
diet
cofactor
development… metabolism… immune… antioxidant… reproduction… digestion
MANGANESE (Mn)
- Can exist in _____ different __________ states
- ____-____% of ingested Mn is absorbed by _________________ tract
- ________ excretion is the predominant route of excretion
11… oxidation
3-5%… gastrointestinal
biliary
Mechanisms in place to maintain Manganese Homeostasis
Mn excess = decreased absorption and increased excretion
Mn deficiency = increase absorption and decreased excretion
3 groups are at risk to excessive Manganese intake from nutritional sources
- Neonates receiving intravenous total parenteral nutrition
- Bypasses the gastrointestinal control of absorption resulting in 100% Mn retention - Patients with hepatic encephalopathy and/or liver failure
- Interferes with excretion of Mn via biliary system - Individuals with iron deficiency
- Can increase Mn body burden
- Due to the use of common transports for uptake by Mn and iron
- Iron deficiency increases the expression of these transporters
Neurotoxic Effects of Manganese:
- No _____________ for the appears of Mn-induced neurotoxic effects in humans
- Can lead to a state of poisoning known as ______________
- Irreversible ___________ condition that resembles ___________ disease
threshold
manganism
progressive… Parkinson’s
Manganism VS Parkinson’s
MANGANISM
- Targets the _____________ (GP) and to a lesser extent the ________________________ (SNc)
- Shows preferential accumulation in the ______________
- Unclear whether manganism is associated with _____________ or ____________ of dopaminergic neurons
globus pallidus… substantia nigra pars compacta
globus pallidus
dgeneration… dysfunction
Manganism VS Parkinson’s
PARKINSON’S
- Targets _________________ (SNc)
- Associated with _______________ of dopaminergic neurons in ____________________
substantia nigra pars compacta
degeneration… substantia nigra pars compacta
Neurotoxic Effects of Manganese: Manganism
- Both manganism and Parkinson’s disease associated with cognitive and emotional problems (4)
intellectual deficits
mood changes
irritability
restlessness and sleep disturbances
Neurotoxic Effects of Manganese: Manganism
- Motor symptoms are distinct between manganism and Parkinson’s, due to different _______
- Manganism: Signs of __________, ________, milder _________ at rest, “_______-like” walk
- Parkinson’s: ____________, ________, _________, ___________ instability
targets
rigidity. .. dystonia… tremors… cock
bradykinesia. .. tremors… rigidity… postural
Neurotoxic Effects of Manganese: Manganism
____________, a treatment for ___________, is NOT very effective
- Current treatments use a combo of _____________ and ____________ therapy
levodopa. .. parkinson’s
levodopa. .. chelation
Manganese Deficiency
- In animals, associated with skeletal abnormalities, such as (3)
- Enlarged joints, deformed legs with thickened and shortened long bones
- Impaired reproductive function and testicular degeneration
- Altered lipid metabolism
Manganese Transport into the brain
- 3 major routes of uptake of manganese into brain tissue
- From the bloodstream across the blood brain barrier
- From the bloodstream through the cerebral spinal fluid
- From the nasal space through the olfactory nerve via olfactory epithelium
Manganese Transport into the Brain: Blood Brain Barrier
May be transported across the blood brain barrier via (4)
- Divalent metal transporter 1 (DMT1)
- Transferrin (Tf)
- Zinc transporters (ZIP8 and ZIP14)
- Calcium Channels
Manganese Transport into the Brain: Blood Brain Barrier: Divalent metal transporter 1 (DMT1)
- Can transport the ____________ form of manganese (Mn+2)
- DMT1 also found in the _______ __________where high levels of Mn accumulation have been reported
- Expression levels may increase with ______
- Increased expression of DMT1 has been found in the _________________ (SNc) of patients with ____________ Disease
- DMT1 also present in _________ which may allow for the uptake of Mn into __________
divalent basal ganglia age Substantia Nigra compacta... Parkinson's neurons... neurons
. Mn Transport into the Brain: Blood Brain Barrier: Transferrin (Tf)
- Transports the ________ form of manganese (Mn+3)
- ________ form of manganese (Mn+2) can be transported but must be __________ to Mn+3 first
- Mn+3 binds to _________ forming a Mn+3-Tf complex
- Transferrin ____________ (TfRs) are expressed in most cells including ________, _________, ____________, and _______________ cells of the blood brain barrier (BBB)
- The Mn+3-Tf complex binds to Tf __________ and enters _____________ cells of the BBB via ______________
- Within _____________cell, Mn+3 disassociates from Tf via ___________ ______________ and is released into the extracellular environment within the brain
- TfRs also found on _________ – may facilitate transport of Mn into neurons
trivalent divalent... oxidized transferrin receptors... neurons... microglia... astrocytes... endothelial receptor... endothelial... endocytosis endothelial... endosomal acidification neurons
Mn Transport into the Brain: Blood Brain Barrier: Zinc Transporters
- Role in Mn transport has been proposed based on __________ models
- No _______________ evidence has been established
- May be more relevant to ___________ route of exposure
in vitro
physiological
inhalation
Mn Transport into the Brain: Blood Brain Barrier: Calcium Channels
- Evidence that _________ ____________ calcium __________ can transport Mn into the brain
- Mechanism similar to that of _______
- Evidence that Mn can cross cell ____________ (including endothelial cells of the BBB) through ________-_____________ calcium channels
voltage gated… channels
lead
membranes… store-operated
Manganese Transport into the Brain: Blood-CSF Barrier
- Evidence that Mn can be transported via the blood-CSF barrier to the brain
- Examples
- Exception
- Hypothesis about exception
Brain regions that demonstrate higher uptake of Mn are adjacent to the ventricles
- EG: hippocampus, visual cortex, striatum
- EXCEPTION: globus pallidus
- Hypothesized that Mn is transported from striatum to globus pallidus
Manganese Transport into the Brain: Olfactory Pathway
3 major pathways facilitate movement of a xenobiotic from nose to brain:
1. Olfactory _________ pathway
- Transport within the _____________________
2. Olfactory ___________ pathway
- Transport along _______________ space around the __________________
- These TWO pathways provides a _____ connection to the CNS that bypasses the ______________________
- _______ _________ __________ pathway
- ________ membrane lining the _______ cavity: high vascularized
- Olfactory nerve pathway
- Transport within the olfactory nerve - Olfactory epithelial pathway
- Transport along perineuronal space around the olfactory nerve
direct. .. blood brain barrier
Nasal mucosa epithelium
Manganese Accumulation: Brain Regions
- Mn preferentially accumulations in brain regions high in ____________, such as the _________________
- Can also be found in regions that don’t have ___________, such as: (3)
- Likely related to the presence of various ___________ __________ in these regions
neuromelanin… basal ganglia
neuromelanin…. striatum, hippocampus, cerebral cortex
transporter proteins
Manganese Accumulation
What is Neuromelanin
an effective chelator with a high affinity for organic amines and metal ions, including Mn
Manganese Accumulation in Neurons & Astrocytes
- significantly higher levels of Mn in ___________
- Within the cells, Mn preferentially accumulates in _____________
- Transport may occur via _________________ (DAT)
- Decreased DAT ________ and _________ in patients chronically exposed to Manganese
astrocytes
mitochondria
dopamine transporter
density… activity
Manganese Efflux Mn can be exported out of the brain via: 1. \_\_\_\_\_\_\_\_\_\_\_\_ 2. \_\_\_\_\_\_\_\_\_\_\_\_ 3. \_\_\_\_\_\_\_\_\_\_\_\_ - Loss of \_\_\_\_\_\_\_\_\_\_\_ mutation in \_\_\_\_\_\_\_\_\_\_\_ gene associated with hereditary form of Mn-induced \_\_\_\_\_\_\_\_\_\_\_\_\_\_
Diffusion
ATPase 13A2
SLC30A10
function…. SLC30A10… parkinsonism
Manganese: Mechanism of Action
- ___________ Stress
- Accumulation of Mn in brain ______________ can inhibit ______ synthesis
- Results in decreased intracellular ______ levels and increased production of ____________________ (ROS)
- Mn can decrease the levels of free ______ and __________ groups in cellular ____________ proteins: Decreases ____________ capacity
Oxidative
mitochondria… ATP
ATP… reactive oxygen species
thiol… hydroxyl… antioxidant… antioxidant
Manganese: Mechanism of Action
- ____________ Stress CON’T
- Mn treatment is associated with an increase in ______________________________ (MnSOD)
- Located primarily in _______________
- Protects against ___________ injury by catalyzing the ____________ of ______________
- This may reduce the risk of ___________ stress?
- This happens in a normal system, but over time the system breaks down and you see dysfunction
Oxidative manganese superoxide dismutase mitochondria oxidative... dismutation... superoxide oxidative
Manganese: Mechanism of Action
- Role of __________
- Mn can substitute for __________ under physiological conditions
- Mn is taken up into ____________ via the _________ __________
- Intra_____________ Mn inhibits ______ synthesis
- Intra_____________ Mn can also inhibit the _______ of ____________
- result in disruption of ___________ integrity
- Which may affect energy production and result in _________ stress and ___________
Calcium
calcium
mitochrondria… calcium uniporter
mitochrondrial… ATP
mitochrondrial… efflux… calcium
membrane
oxidative… apoptosis
Manganese: 5 Mechanisms of Action
- Oxidative Stress
- Role of Calcium
- Exitotoxicity
- Dopaminergic dysfunction
- Alpha-synuclein (aSyn)
Manganese: Mechanism of Action
- _____________
- Accumulation of Mn in ____________ can increase the potential for excitotoxicity via altered ___________ ____________
- Mn decreases the ability of ___________ to clear ____________ from _________________ space
- Increases __________ in the __________ and results in overactivation of ____________ receptors
- Mn increases the sensitivity of ___________ receptors to ____________
- Results in ______________ of receptors
- Blocking ________ receptors prevents Mn-induced excitotoxicity
- Mn also disrupts the __________-___________ cycle
- Neurons cannot synthesize ___________ or ______
- Astrocytes take up both neurotransmitters and convert them to _____________
- ___________ is release by astrocytes which is taken up by neurons
- Serves as precursor to ___________ or _______
Exitotoxicity
astrocytes. .. glutamate metabolism
astrocytes. … glutamate…. extracellular
glutamate. .. synapse… glutamate
glutamate… glutamate
overactivation
NMDA
glutamate-glutamine glutamate... GABA glutamine glutamine glutamate... GABA
Manganese: Mechanism of Action
- _______________ Dysfunction
- ________ deficits associated with Mn exposure suggest the disruption of this system
- Hypothesized that the ______ deficits may be related to reduced ___________ (DA) availability at the synapse
- Due to impaired __________ or altered DA __________ (DAT)
Dopaminergic
motor
motor… dopamine
release… reuptake
Manganese: Mechanism of Action What is alpha-synuclein - can interact with.... - major component in... - primarily exists in...
a small protein that is expressed in the cytosol and presynaptic terminals near synaptic vesicles
- Can interact with lipid membranes
- Major component in Lewy bodies (hallmark of PD and other neurodegenerative disorders)
- Primarily exists in unfolded state
Manganese: Mechanism of Action
- _____________
- ____________ has a _______ affinity for many metals
- Mn has a _____ affinity for ___________
Evidence that __________ may protect against Mn-induced neurotoxicity:
- __________ can act as a metal scavenger – acting as a Mn ________
- Likely only protective ______ on with respect to Mn exposure
Evidence _________ may contribute to Mn-induced neurotoxicity:
- Mn exposure may increase ____________, ____________, and ____________ of _________
- May contribute to ___________________
α-Synuclein (aSyn)
aSyn… high
low… aSyn
aSyn
aSyn… store
early
aSyn
misfolding, aggregation, expression… aSyn
neurodegeneration
BIOTOXINS
What is a biotoxin
Natural toxins produced by living organisms
BIOTOXINS
6 classes of toxin-producing organisms
Viruses Bacteria Fungi Protozoa Plants Animals Algae
BIOTOXINS
- What is Tetrodotoxin (TTX)
- Found in…
- Historically found in seafood harvested in more…
- Produced by…
- Bacterial strains of the family __________________
- Organisms become contaminated with the bacteria by…
Therefore, Pufferfish born and raised in captivity _____ produce TTX
- Potent acute neurotoxin, extremely toxic
- Found in puffer fish, blue ringed octopus, rough-skinned newts, moon snails
- tropical waters in the Pacific Ocean
- produced by commensal bacteria found within the organism, not by the organism itself
Vibrionacease
eating food containing this bacteria
DON’T
BIOTOXINS
- Mutually Beneficial Relationship between TTX and Host Organisms
-Why aren’t host organisms affected?
Bacteria get a safe place to live, eat, and reproduce
Host organisms use the toxin for predation or defence
Single point mutation in the amino acid sequence in the voltage gated sodium channel
- TTX cannot bind to these mutated channels
BIOTOXINS
TTX: 3 Stages of Poisoning
Stage 1: Numbness
- Numbness in the face and extremities
- Sensations of lightness or floating
Stage 2: Increasing paralysis
- Some victims are unable to move, sitting may be difficult
- Increasing respiratory distress
- Speech is affect
Stage 3: Death
- Usually occurs within 4 to 6 hours
- Due to respiratory paralysis
BIOTOXINS: TTX
Structure of Voltage gated sodium channels (VGSC)
- Integral membrane protein consisting of ___ and ___ subunits
- Made up of ___ ____________ transmembrane domains
- Each of the domains are subdivided into:
- A ________ sensing domain (segments S1-S4)
- A _____ forming domain (segments S5-S6)
β and α
4 homologous
voltage
pore
Biotoxins: TTX: Mechanism of Action
- Highly ________ molecule
- Binds to _______ on VGSC
- Temporarily ________ the VGSC, prevents ________ of sodium, results in the inhibition of membrane ______________, prevents the generation of an ___________________
charged
site 1
blocks… influx… depolarization… action potential
Biotoxins: TTX: Mechanism of Action
- TTX prevents the generation of an action potential by blocking VGSC
- This can prevent the contraction of __________ and __________ _________
- Can lead to ______________ failure, ________ arrest, muscle ___________, and death
skeletal. .. cardiac muscles
respiratory. .. cardiac… paralysis
BIOTOXINS: Harmful Algal Blooms (HABs)
- algal blooms composed of…
- They can occur when…
- HABs can deplete the… block the…. and clog…
- Some HABs release toxins that are dangerous to animals and humans who…
phytoplankton known to naturally produce biotoxins
certain types of microscopic algae grow quickly in water
oxygen in the water… sunlight that other organisms need to live… clog fish gills
feed directly or indirectly on them
BIOTOXINS: Harmful Algal Blooms (HABs)
7 things that cause HABs
Eutrophication Warm temperatures Lots of sunlight Runoff Farming Human sewage Pesticides
BIOTOXINS: Harmful Algal Blooms (HABs)
What is Eutrophication
Occurs when bodies of water become overly enriched with minerals and nutrients
Leads to excessive growth
BIOTOXINS: Harmful Algal Blooms (HABs)
Climate change has had a big impact on the presence and location of HABs
Number of toxic HABs are increasing
- Due to increasing water temperature
Location of HABs is changing
- HABs are now occurring more temperate waters
- Due to increasing water temperature
BIOTOXINS: Harmful Algal Blooms (HABs)
Toxins are produced by 3 types of algae
Diatoms
Dinoflagellates
Cyanobacteria
BIOTOXINS: Algal Toxins
Toxins can be classified based on the body of water they are found in
5 Marine algal toxins
Paralytic shellfish poisoning (saxitoxins)
Amnesic shellfish poisoning (domoic acid)
Ciguatera toxins
Diarrheic shellfish poisoning (okadaic acid)
Neurotoxic shellfish poisoning (brevetoxin)
BIOTOXINS: Algal Toxins
Toxins can be classified based on the body of water they are found in
5 Freshwater algal toxins
Anatoxin Nodularin Microcystins Saxitoxins B-methylamino-L-alanine
BIOTOXINS: Algal Toxins
Toxins can also be classified depending on the vectors that they contaminant
- 4 Shellfish poisonings
- 1 fish poisoning
Shellfish
- Paralytic shellfish poisoning
- Neurotoxic shellfish poisoning
- Diarrheic shellfish poisoning
- Amnesic shellfish poisoning
Fish
- Ciguatera
BIOTOXINS: Algal Toxins
Humans can be exposed to algal toxins via (3)
- The consumption of contaminated seafood or drinking water
- Swimming in contaminated water
- Breathing in aerosolized algal toxins
BIOTOXINS: Algal Toxins: Seafood Vectors
- __________ accumulate toxins more quickly than other types of shellfish
- ____________ and ___________ store toxins longer than other species
mussels
Varnish clams and butter clams
Paralytic Shellfish Poisoning (PSP)
- _____ analogs identified
- Most well known analog: ___________ (STX)
- Produced by both ___________ and ________ algal species
19
saxitoxin
freshwater… marine
BIOTOXINS: Algal Toxins: Saxitoxin
The Red Tide
Not always toxic!
Not always possible to see when STX levels are elevated
Only occurs when dinoflagellates rapidly accumulate turning the water a red/brown colour
BIOTOXINS: Algal Toxins: Saxitoxin
Exposure symtpoms
Disorientation, dizziness, memory loss, headache, vomiting, numbness (tongue, lips, fingertips), weakness, diarrhea, motor incoordination, diplopia (double vision), swallowing difficulties, flaccid paralysis, respiratory failure