Transcript Parkinson`s Disease

early-onset forms of
Parkinson’s disease
Dr. Pupak Derakhshandeh (PhD)
Assis. Prof. Med. Sci. of Tehran
Univ.
Parkinson's Disease
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Parkinson's Disease
 one of the most common human
neurodegenerative diseases
 progressive
 affecting one of the regions of the brain
controlling movement
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The most common symptoms
 Tremor
 muscular stiffness
 and slowness of movement
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 there are different types of parkinsonism
 the most common condition today is the
one first recognized in 1817 by James
Parkinson
 At present there is no cure
 but treatments do exist and are available
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Dopamine
 symptoms are due to a deficiency of the brain
chemical:
 Dopamine
 the nerve cells containing dopamine: die
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Dopamine
 As a chemical messenger, and is similar
to adrenaline
 Dopamine affects brain processes that
control movement, emotional response,
and ability to experience pleasure and
pain
 Regulation of dopamine: plays a crucial
role in our mental and physical health
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Dopamine in substantia nigra
 Neurons containing the neurotransmitter dopamine
are clustered in the midbrain
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L-DOPA
 In Parkinson's disease, the
dopamine- transmitting neurons in
this area die.
 To help relieve their symptoms, we
give these people L-DOPA, a drug
that can be converted in the brain
to dopamine
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Dopamine - A Neurotransmitter
One of the neurotransmitters playing a
major role in addiction is dopamine
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Addiction and dopamine
 In certain areas of the brain when dopamine is
released
 it gives one the feeling of pleasure or satisfaction
 person will grow a desire for the satisfaction
 To satisfy that desire the person will repeat
behaviors that cause the release of dopamine
 For example food, smoke,… release dopamine
 these behaviors can result in addiction due their
effect on dopamine!
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How the addiction begins? e.g. Cocaine
 Cocaine chemically inhibits the natural dopamine
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cycle
after dopamine is released, it is recycled back into a
dopamine transmitting neuron
cocaine binds to the dopamine
and does not allow it to be recycled
it floods certain neural areas
The flood ends after about 30 minutes
the person is left yearning to feel as he or she once
did
person is constantly trying to repeat the feeling that
he or she had the first time
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How the addiction begins?
 After the first time, the person expects the
effect, thus less dopamine is released
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the experience is less satisfying
because dopamine is also released when
something pleasurable yet
unexpected occurs!
 This principal is the foundation of why
gambling releases dopamine!
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incidence
 The incidence of Parkinsonism increases with
age
 and is uncommon in people younger than forty
 Parkinson's disease affects both men and
women
 across all ethnic groups and is a serious
health problem in all the world
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1-I) Slowness of movement
 This
is the most disabling symptom
 The
slowness makes it difficult to get out
of a chair or turn in bed
 Fine
movements such as buttoning
clothing, handwriting, and using a fork or
knife may become difficult
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1-II) Slowness of movement

Later, the person appears to be in slow motion
and if not treated may become virtually frozen
like a statue

Because of the enormous energy it takes to
overcome slowness, the person with Parkinson's
disease often complains of being "weak"
although there is no true muscular weakness
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2) Tremor
 Tremor or shaking occurs in about two-thirds
of people with Parkinsonism
 the most visible and obvious sign of the
disease
 Parkinson tremor usually affects the hands
and feet
 it sometimes involves the lips, tongue, and
jaw
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3) Muscle stiffness
 Stiffness combined with slowness
 may cause aching muscles and joints,
especially in the shoulders
 This is sometimes misinterpreted as "arthritis"
or "bursitis”
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4) Masked face
 showing little or no emotion through facial
expression
 Blinking and spontaneous eye movements
are less frequent
 This can be misinterpreted as lack of interest
or depression
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5) Walking difficulties
 The gait may be slow with short steps
 It is common to have difficulties with balance
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6) Speech problems
 About one half of all individuals with
Parkinson's disease develop difficulty with
their speech
 Communication can be complicated further
by a fast mumbling speech with
uncontrollable repetitions of the first syllable
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7) Swallowing difficulties
 difficulty eating because their ability to
swallow has become impaired
 Food may collect in the mouth or the back of
the throat resulting in choking or coughing
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Parkinson’s disease in the family
synuclein gene
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Alpha-synuclein
 Alpha-synuclein is part of the synuclein family
including beta- and gamma-synuclein
 Synucleins are very common in the brain
 SNCA located on chrmosome 4
 expresses the140-amino acids (OMIM*163890)
 (http://health.upenn.edu/cndr/research1/tausyn/tausyn.htm)
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Familiar Parkinsons
 No alterations in alpha-synuclein gene
dosage observed in sporadic Parkinsons
(Movement disorders disease : official journal of the Movement
Disorder Society. 2006 Mar 21)
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Synuclein (SNCA)
 point mutations seen in familial
Parkinson's disease (PD)
 are rarely found in sporadic disease
 usually develop symptoms around
age 45 (AD)
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Familiar Parkinson’s disease
 Parkinson’s disease in familiar except for its:
early onset
 a larger than expected number of people
with Parkinson’s disease
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Lewy bodies
 similar to the beta-amyloid plaques found in
Alzheimer's / and PD patients
 The Lewy bodies lead to loss of neurons
 then dopamine (a neurotransmitter)
 and finally loss of motor control
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 defected alpha-synuclein product

the primary component of Lewy bodies in all
PD patients
 two different a-synuclein missense
mutations (A30P and A53T) are associated
with:
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rare, autosomal dominant
early-onset PD and have been shown to
form fibrils
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PD-linked mutations (A30P and A53T)
 correlated to the onset of disease
phenotype
 in vitro a-synuclein oligomerization:
 suggesting
that the process of asynuclein fibrillization may initiate
neurodegeneration
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Synuclein (SNCA)
 synuclein mRNA expression : play
a role in the etiology of the disease
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Exception:
Movement Disorders, Vol. 20, No. 5, 2005
 study demonstrates that -synuclein expression
levels were not significantly different between
sporadic PD and healthy controls similar in age,
gender, and race.
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Dosage effect on clinical phenotype
 even in the absence of mutations detectable
by sequence analysis
 simple multiplications of SNCA can cause
autosomal dominant forms of PD
 a dosage effect on clinical phenotype, with
duplication of the gene resulting in a
phenotype similar to PD
 but triplication resulting in early-onset
parkinsonism with dementia
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 neither mutations in the coding region of
SNCA
 nor over expression of the gene due to
multiplication
 appear to be common causes of PD
 It remains possible:
 other genetic factors may influence synuclein mRNA expression
 play a role in the etiology of the disease
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an association between the polymorphic
sequence repeat in the promoter region of
SNCA and PD risk
(Mellick GD, Maraganore DM, Silburn PA. Australian data and
meta-analysis lend support for alpha-synuclein (NACP-Rep1) as a
risk factor for Parkinson's disease. Neurosci Lett 2005; 375: 112116. )
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mitochondrial
dysfunction
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The role of mitochondrial dysfunction
in Parkinson's disease
 functions of DJ1, PINK1 and OMI/HTRA2
 which are all associated with the mitochondria
in cellular protection against oxidative damage
(Nature Reviews Neuroscience 7, 207-219 (March 2006) |
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Familial forms of PD
 11 genetic loci with linkages to PD have been
established, and for six of these (PARK 1/4,
2, 6, 7, 8, and 9), the responsible gene has
been identified
 conclusively determined to cause familial
forms of PD (Ramirez et al. 2006)
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PARK7 (AR)
 DJ-1, and several point mutations in this
part of PARK 7 gene have been
associated with an autosomal recessive
early onset form of PD
(Tang et al. 2006).
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The DJ-1 mutated protein
 encodes a ubiquitous, highly conserved
protein
 DJ-1 mutations are associated with PARK7
 a monogenic form of human
PARKINSONISM
 The function of the DJ-1 protein:
 in the oxidative stress response
 loss of DJ-1 function leads to
neurodegeneration
& PARKINSON's disease
(Science 10 January 2003:Vol. 299. no. 5604, pp. 256 – 259)
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PARKINSON DISEASE 6,
AUTOSOMAL RECESSIVE
EARLY-ONSET; PARK6
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PARK6
 Localization of a novel locus for
autosomal recessive early-onset
parkinsonism:
 on human chromosome 1p35-p36
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PARK6
 unrelated families with autosomal recessive
PD from various regions in Asia that showed
linkage to the PARK6 locus
 Families: consanguineous
 Age at onset ranged from 18 to 56 years,
although most had onset in the third or fourth
decades
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Autosomal recessive PD from
 mutations affecting the PINK1 kinase domain in
PARK6 families
 onset in patients with PINK1 mutations was earlier
and increased reflexes were found more frequently
than in patients without PINK1 or parkin mutations
(Hatano et al., 2004 ; Healy et al., 2004 ; Rogaeva et al., 2004 ;
Rohe et al., 2004 ; Valente et al., 2004a ; Valente et al., 2004b ;
Bonifati et al., 2005 ; Klein et al., 2005)
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pedigrees of families with PINK1
mutations (AR)
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PINK1 mutations
 All missense (C125G, E240K, L369P, G386A
and G409V) mutations replace highly
conserved residues
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Relative frequencies of patients with PINK1 or parkin mutations and
without PINK1 and parkin mutations according to the age at onset
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PINK1 mutations
 that heterozygous mutations in genes
(compound heterozygous):
 autosomal recessive forms with an early
onset can also cause later onset Parkinson's
disease !
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An Exception !
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A) novel homozygous nonsense PINK1 mutation in
exon 3(C99A) leading to a loss of kinase domain
of the PINK1 protein (Tyr258Stop).
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B: A novel heterozygous missense mutation in the
kinase domain of exon 4 (G62A) leading to an amino
acid substitution (Ala280Thr).
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Molecular Findings in Familial
Parkinson Disease Park2 gene (AR)
 Mutations in Park2 gene account for 38% of
the families with recessive parkinsonism in
Spain
 Heterozygous carriers of a single Park2
mutation either were asymptomatic or
developed clinical symptoms in late
adulthood
 (Arch Neurol. 2002;59:966-970)
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