Download path430_826-week10-PD

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project

Document related concepts

Optogenetics wikipedia , lookup

Neuromuscular junction wikipedia , lookup

Feature detection (nervous system) wikipedia , lookup

Visual selective attention in dementia wikipedia , lookup

Premovement neuronal activity wikipedia , lookup

Synaptic gating wikipedia , lookup

Neurogenomics wikipedia , lookup

Aging brain wikipedia , lookup

Molecular neuroscience wikipedia , lookup

Channelrhodopsin wikipedia , lookup

Neuropsychopharmacology wikipedia , lookup

Alzheimer's disease wikipedia , lookup

Parkinson's disease wikipedia , lookup

Clinical neurochemistry wikipedia , lookup

Biochemistry of Alzheimer's disease wikipedia , lookup

Dementia with Lewy bodies wikipedia , lookup

Transcript
Parkinson’s Disease
Pathology 430/826
The Molecular Basis of Disease
Neurological Genetics
9th March 2015
Dr. John Rossiter
[email protected]
Astroglial cells (Astrocytes)
Oligodendrocyte
Neurodegenerative Diseases
• A heterogeneous group of slowly progressive neurological
diseases.
• Individual disorders traditionally classified on the basis of their
clinical and pathological features.
• Characterised by selective loss of certain anatomically and/or
physiologically related systems of neurons.
Some examples:
• Cerebral Cortex
- Alzheimer’s disease
- Pick’s disease
• Basal Ganglia
- Huntington’s disease
- Parkinsons disease
• Motor System
- ALS
• Spinocerebellar Syst. - Friedreich’s ataxia
• Peripheral nerves
- Charcot-Marie-Tooth
• Note: the above list indicates regions of preferential, but not
exclusive, neuronal loss. For example, in AD there is also
degeneration and loss of neurons in subcortical structures and
brainstem, and in HD there is also neuronal loss in the cerebral
cortex.
• Disorders such as Alzheimer’s disease, Parkinson’s
disease (and ALS) likely result from the interaction of a
variety of age-related, genetic and environmental factors.
• These factors ‘converge’ to result in a similar clinicopathological phenotype.
• Identification of gene mutations in rare familial cases gives
important insights into the pathogenesis of the much
commoner sporadic forms of these diseases.
Some important recurring themes in the pathogenesis of
neurodegenerative diseases
• Increasing age is a major risk factor, likely in part related to
defects in mitochondrial energy metabolism.
• Abnormal protein folding and aggregation appears to play a key
pathogenetic role in many neurodegenerative diseases.
• Synaptic dysfunction is likely an important early event.
• Neuronal cell death does eventually occur, but neurons have
likely been stressed and adaptive/maladaptive for months or
years before this.
• Excitatory amino acid toxicity (excitotoxicity) is probably an
important pathogenetic factor, especially in HD and ALS.
J.J. Palop et al, Nature 19 Oct 2006, 768-773
A strong case can be made for understanding
many Neurodegenerative diseases as:
‘Protein Aggregation Disorders’
Abnormal protein folding and resulting
aggregation causes:
Loss of normal protein function
Gain of Toxic function
Dr. James Parkinson
Dopaminergic projection systems
Blumenfeld Fig. 14.10
W Matsuda et al. J Neurosci. 14 Jan 2009
JD Surmeier et al., Neuroscience 198 (2011)221-231
Loss of pigmented
dopaminergic neurons in
the substantia nigra and
a Lewy body inclusion
in the cytoplasm of a
surviving neuron
*
*
Nucleus
Two Lewy bodies in the cytoplasm
of a neuron in the pars compacta of
the substantia nigra
*
Normal rostral pons
Advanced PD
The sections of the rostral pons above shows the normal
locus bilaterally containing pigmented noradrenergic
neurons and marked depigmentation of these nuclei in a
case of advanced Parkinson’s disease (right panel).
Noradrenergic projection systems
Blumenfeld Fig. 14.11
Mutations in the alpha-synuclein gene cause rare
autosomal dominant cases of familial AD
Science, 27 June 1997
In the common (sporadic) form of PD, Lewy bodies are formed
predominantly from aggregates of alpha-synuclein (normal gene but
abnormal protein metabolism)
Intense immunoreactivity of Lewy bodies for alpha-synuclein protein. Nature, Aug. 1997
α-synuclein-immunoreactive Lewy bodies (blue arrows) and Lewy neurites
(yellow arrows for representative examples) in the midbrain tegmentum.
α-synuclein
• Both mutations in alpha synuclein and overproduction of the
normal protein can directly cause PD
• Role of alpha synuclein in the much commoner sporadic forms
of PD ?
• A polymorphic microsatellite repeat in the alpha synuclein
promoter associated with sporadic PD in some studies, but not
in others
α-Synuclein
• α-synuclein is a small protein (140 amino acids).
• It is highly expressed in neurons, especially at presynaptic nerve
endings.
• It has several normal functions, including the regulation of vesicle
dynamics at presynaptic nerve endings and the fusion and fission of
mitochondria. It also appears to have a regulatory role in autophagy.
• In Parkinson’s disease and other ‘Synucleinopathies’ individual αsynuclein molecules change their configuration and this promotes the
formation of oligomers and subsequently insoluble polymers that form
Lewy bodies and Lewy neurites.
• PD pathogenesis probably results from a combination of loss of normal
function and gain of toxic function of α-synuclein, with monomers and
oligomers likely being the most toxic form of altered α-synuclein .
Science, 21May 2004
B. Levine, Nature, 2007; 446:746
In ‘Diffuse Lewy body disease’ / ‘Dementia with Lewy bodies’, Lewy bodies
and neurites are found more extensively distributed in the CNS, especially
in the cerebral cortex.
Third report of the DLB consortium. Neurology 65 (2005) 1863-71
*
H&E stain
*
Ubiquitin immunostain
α-synuclein-immunostain
Cortical Lewy bodies in a case of Diffuse Lewy body disease
Cortical Lewy bodies are
only the ‘tip of the iceberg’.
A sensitive immunodetection technique shows
diffuse α-synuclein
aggregation in the cerebral
cortex of a DLB case versus
normal brain.
Kramer et al., J. Neuroscience, Feb 2007
Dr. James Parkinson