Early-onset forms of Parkinson’s disease Dr. Pupak Derakhshandeh (PhD) Assis. Prof. Med. Sci. of...
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Transcript of Early-onset forms of Parkinson’s disease Dr. Pupak Derakhshandeh (PhD) Assis. Prof. Med. Sci. of...
early-onset forms of
Parkinson’s disease
Dr. Pupak Derakhshandeh Dr. Pupak Derakhshandeh (PhD)(PhD)
Assis. Prof. Med. Sci. of Tehran Assis. Prof. Med. Sci. of Tehran UnivUniv.
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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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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-DOPAIn 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 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 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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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 diseaseusually 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: 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 a-
synuclein fibrillization may initiate neurodegeneration
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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: 112-116. )
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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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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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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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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)