Transcript Parkinson disease

March 5th, 2007
MCB 135k Discussion Lecture 1416, 18
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Neurons that can proliferate into adulthood include:
•
•
•
Neuroblasts in the subventricular zone (SVZ) and subgranular
layer which migrate towards the olfactory bulb and hippocampus
respectively
Dormant Neuroprogentior cells
Neuroglia
The rate of degeneration far exceeds the ability of these cells to
compensate for neuronal loss
Research seeking to activate/increase proliferation of these cells to
regenerate lost brain tissue (neural stem cells) in
neurodegenerative diseases
Major Function of the Nervous System
The major function of the CNS is to
communicate & to connect:
•with other CNS cells
•with peripheral tissues (outside CNS)
•with the external environment (including physical and social
environments)
This communication regulates:
•Mobility
•Sensory information
•Cognition
•Affect and mood
•Functions of whole-body systems
Glial Cells:
Astrocyte- structural/nutritional
support for neurons
Oligodendrocyte- sheath
axons, allow for faster action
potential transmittanceprotective roles
Microglia- neuronal immune
cells
Neurons:
Axons- transmit signal, only one per
cell
Dendrites- receive signal, numerous
projections per cell
• In normal aging, moderate neuronal loss occurs in the:
Locus Ceruleus: nucleus in the brain stem (inferior to the cerebellum in the
caudal midbrain/rostral pons) apparently responsible for the physiological
reactions involved in stress and panic. This nucleus is the major location
of neurons that release norepinephrine throughout the brain. Implicated in
wide ranging disorders: depression, panic, anxiety disorders,
Posttraumatic stress disorder
Substantia Nigra: A dark band of gray matter deep within the brain where
cells manufacture the neurotransmitter dopamine for movement control.
Degeneration of cells in this region may lead to a neurologic movement
disorder such as Parkinson's disease
Nucleus basalis of meynert:Lateral part of the tuber cinereum that
provides most of the acetylcholine to the cerebral cortex. Decrease in
production seen in Alzheimer’s disease and Lewy Body dimentia.
Hippocampus: The part of the brain that assists in storing memory by
sorting and sending new bits of information to be stored in appropriate
sections of your brain and recalling them when necessary
Major functional deficits/ pathologies involve:
Motility (e.g. Parkinson’s Disease)
Senses and communication
Cognition (e.g. dementias)
Affect and mood (e.g. depression)
Blood circulation (stroke, multi-infarct dementia)
Pathological and Cellular
Changes with Normal Aging
• Increased intracellular deposits of lipofuscin
• Intracellular formation of PHFs
• Accumulation of amyloid deposits in the neuritic
plaques and surrounding the cerebral blood vessels
• Accumulation of Lewy bodies
• Cell death (apoptosis, necrosis)
Key terms:
Lipofuscin: Lipofuscin are brown pigment granules representing lipidcontaining residues of lysosomal digestion and considered one of the
aging or "wear and tear" pigments; found in the liver, kidney, heart
muscle, adrenals, nerve cells, and ganglion cells.
PHF: Paired helical filaments (PHF) are abnormal, approximately 20-25nm wide periodically twisted filaments, which accumulate in Alzheimer's
disease (AD) brain and other neurodegenerative disorders, including
corticobasal degeneration (CBD). PHF are primarily composed of
highly phosphorylated tau protein, proteins that interact with and
stabilize microtubules, promote tubulin assembly (MAP).
Amyloid:insoluble fibrous protein aggregations sharing specific structural
traits (cross-beta quaternary structure) commonly found in Alzheimer’s
disease. Main constituent of amyloid plaques are Abeta (Amyloid
beta)proteins, formed after cleavage of amyloid prescursor protein
(APP). Autosomal-dominant mutations can cause early onset AD.
Lewy Body: abnormal aggregates of protein that develop inside nerve
cells. A Lewy body is composed of the protein alpha-synuclein
associated with other proteins such as ubiquitin, neurofilament protein,
and alpha B crystallin. Linked to Parkinson’s disease.
PHF
Lipofuscin
Lewy
Body
Parkinson’s Disease:
Parkinson's disease (also known as Parkinson disease or
PD) is a degenerative disorder of the central nervous system
that often impairs the sufferer's motor skills and speech
Symptoms:
•Tremor
•Rigidity
•Bradykinesia/akinesia: respectively, slowness or absence of
movement
•Postural Instability
•Gait abnormalities
•Fatigue
•Soft speech/Drooling
Short video on Parkinson’s Disease and GDNF therapy:
http://www.youtube.com/watch?v=gnDHMveS9_M
•Results from the loss of pigmented dopamine-secreting (dopaminergic)
cells
•Neurons project to the striatum and their loss leads to alterations in the
activity of the neural circuits within the basal ganglia that regulate
movement, in essence an inhibition of the direct pathway and excitation
of the indirect pathway.
•The direct pathway facilitates movement and the indirect pathway
inhibits movement, thus the loss of these cells leads to a hypokinetic
movement disorder.
•The lack of dopamine results in increased inhibition of the ventral lateral
nucleus of the thalamus, which sends excitatory projections to the motor
cortex, thus leading to hypokinesia.
•The mechanism by which the brain cells in Parkinson's are lost may
consist of an abnormal accumulation of the protein alpha-synuclein
bound to ubiquitin in the damaged cells. The alpha-synuclein-ubiquitin
complex cannot be directed to the proteosome. This protein
accumulation forms proteinaceous cytoplasmic inclusions called Lewy
bodies.
Alzheimer's disease (AD), also known simply as Alzheimer's, is a
neurodegenerative disease characterized by progressive cognitive
deterioration together with declining activities of daily living and
neuropsychiatric symptoms or behavioral changes. It is the most
common type of dementia. The ultimate cause of the disease is
unknown
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Three major competing hypotheses exist:
"cholinergic hypothesis" and suggests that AD begins as a
deficiency in the production of the neurotransmitter acetylcholine
tau protein abnormalities initiate the disease cascade,
supported by the long-standing observation that deposition of
amyloid plaques do not correlate well with neuron loss
beta amyloid deposits are the causative factor in the disease
- cytotoxicity of mature aggregated amyloid fibrils, which are
believed to be the toxic form of the protein responsible for
disrupting the cell's calcium ion homeostasis and thus
inducing apoptosis
YOUNG
OLD
Reaction Time (msec)
800
600
400
200
0
2 Letters
6 Letters
Neural recruitment
LESS
FAST
--------------------->
--------------------->
MORE
SLOW
Information processing speed
Reaction Time (msec)
1500
1250
Old
Young
1000
750
500
2
6
2
Memory Load
6
YOUNG
UNDER
RECRUITMENT
YOUNG
OLD
ELDERLY
NON-SELECTIVE
RECRUITMENT
OVER
RECRUITMENT
FASTEST
YOUNG
OLD
SLOWEST
Apoptosis
Programmed Cell Death - executed in such a way as to safely
dispose of cell corpses and fragments.
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•Evolutionarily conserved
•Occurs in all multicellular animals studies (plants too!)
•Stages and genes conserved from nematodes (worms)
and flies to mice and humans
•Important in embryogenesis
•Selection/ Eliminates non-functional cells
•Immunity-eliminates dangerous cells
•Organ size - eliminates excess cells
•Tissue remodeling - mammary gland/ prostate
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Lack of proper apoptosis during development can lead
to fused toes / fingers
APOPTOSIS: control
Receptor pathway (physiological):
FAS ligand
Death receptors:
(FAS, TNF-R, etc)
TNF
Death
domains
Adaptor proteins
Pro-caspase 8 (inactive)
Pro-execution caspase (inactive)
MITOCHONDRIA
Caspase 8 (active)
Execution caspase (active)
Death
APOPTOSIS: control
Intrinsic pathway (damage):
Mitochondria
BAX
BAK
BOK
BCL-Xs
BAD
BID
B IK
BIM
NIP3
BNIP3
Cytochrome c release
Pro-caspase 9 cleavage
Pro-execution caspase (3) cleavage
BCL-2
BCL-XL
BCL-W
MCL1
BFL1
DIVA
NR-13
Several
viral
proteins
Caspase (3) cleavage of cellular proteins,
nuclease activation,
etc.
Death
APOPTOSIS: control
Physiological
receptor pathway
Intrinsic
damage pathway
MITOCHONDRIAL SIGNALS
Caspase cleavage cascade
Orderly cleavage of proteins and DNA
CROSSLINKING OF CELL CORPSES; ENGULFMENT
(no inflammation)
APOPTOSIS: Role in Disease
TOO MUCH: Tissue atrophy
Neurodegeneration
Thin skin
etc
TOO LITTLE: Hyperplasia
Cancer
Athersclerosis
etc
APOPTOSIS: Role in Disease
AGING
Aging --> both too much and too little apoptosis
(evidence for both)
Too much (accumulated oxidative damage?)
---> tissue degeneration
Too little (defective sensors, signals?
---> dysfunctional cells accumulate
hyperplasia (precancerous lesions)
Discussion questions:
What are the function of glial cells in the nervous system?
What are the similarities and differences between
Parkinson’s disease and Alzheimer’s diseases?
What does fMRI data reveal about memory tasks in old
versus young individuals?
What roles does apoptosis have in disease? How can
apoptosis be characterized as an example of antagonistic
pleiotropy?