early-onset forms of Parkinson’s disease Dr. Pupak Derakhshandeh (PhD) Assis. Prof. Med. Sci. of Tehran Univ Dr. Pupak Derakhshandeh (PhD) Assis. Prof. Med. Sci. of Tehran Univ.

Parkinson's Disease

one of the most common human neurodegenerative diseases progressive degenerative disorder affecting one of the regions of the brain controlling movement

The most common symptoms Tremor muscular stiffness and slowness of movement

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

Dopamine symptoms are due to a deficiency of the brain chemical: Dopamine the nerve cells containing dopamine: die

Dopamine - A Neurotransmitter One of the neurotransmitters playing a major role in addiction is dopamine As a chemical messenger, dopamine 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 Neurons containing the neurotransmitter dopamine are clustered in the midbrain in an area called the substantia nigra 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

substantia nigra Neurons containing the neurotransmitter dopamine are clustered in the midbrain in an area called the substantia nigra

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

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 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

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

Muscle stiffness Stiffness combined with slowness may cause aching muscles and joints, especially in the shoulders This is sometimes misinterpreted as "arthritis" or "bursitis”

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

Walking difficulties The gait may be slow with short steps It is common to have difficulties with balance

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

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

Parkinson’s disease in the family synuclein gene

No alterations in -synuclein gene dosage observed in sporadic Parkinson's (Movement disorders disease : official journal of the Movement Disorder Society Mar 21)

Synuclein (SNCA) point mutations seen in familial Parkinson's disease (PD) are rarely found in sporadic disease usually develop symptoms around age 45 (AD) synuclein mRNA expression : play a role in the etiology of the disease a SNP in alpha-synuclein (SNCA), showed the strongest association with PD (Hum Mul Gent 2006 Apr 1;15(7): Epub 2006 Feb 24)

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 acid protein alpha- synuclein (OMIM*163890)OMIM* (

Parkinson’s disease in famillier except for its: early onset and very fulminant course a larger than expected number of people with Parkinson’s disease Gene: PARK4

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

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

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: )

Lewy bodies similar to the beta-amyloid plaques found in Alzheimer's patients) The Lewy bodies lead to loss of neurons then dopamine (a neurotransmitter) and finally loss of motor control

1. First, a-synuclein is the primary component of Lewy bodies in all PD patients 2. 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

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

mitochondrial dysfunction

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, (March 2006) |

The DJ-1 gene 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 no. 5604, pp. 256 – 259)

PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET; PARK6

PARK6 Localization of a novel locus for autosomal recessive early-onset parkinsonism: on human chromosome 1p35-p36

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

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)

pedigrees of families with PINK1 mutations (AR)

PINK1 mutations All missense (C125G, E240K, L369P, G386A and G409V) mutations replace highly conserved residues

Relative frequencies of patients with PINK1 or parkin mutations and without PINK1 and parkin mutations according to the age at onset

PINK1 mutations that heterozygous mutations in genes: autosomal recessive forms with an early onset can also cause later onset Parkinson's disease !

Molecular Findings in Familial Parkinson Disease 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: )