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.

2 Parkinson's Disease

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

4 The most common symptoms Tremor muscular stiffness and slowness of movement

5 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

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

7 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

8 Dopamine in substantia nigra Neurons containing the neurotransmitter dopamine are clustered in the midbrain

9 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

10 Dopamine - A Neurotransmitter One of the neurotransmitters playing a major role in addiction is dopamine

11 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!

12 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

13 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!

14 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

15 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

16 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

17 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

18 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”

19 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

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

21 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

22 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

23 Parkinson’s disease in the family synuclein gene

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 acids (OMIM*163890)OMIM* (

25 Familiar Parkinsons No alterations in alpha-synuclein gene dosage observed in sporadic Parkinsons (Movement disorders disease : official journal of the Movement Disorder Society Mar 21)

26 Synuclein (SNCA) point mutations seen in familial Parkinson's disease (PD) are rarely found in sporadic disease usually develop symptoms around age 45 (AD)

27 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

28 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

29 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

30

31 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

32

33 Synuclein (SNCA) synuclein mRNA expression : play a role in the etiology of the disease

34 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.

35 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

36 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

37 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: )

38 mitochondrial dysfunction

39 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) |

40

41 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)

42 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).

43 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 no. 5604, pp. 256 – 259)

44 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET; PARK6

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

46 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

47 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)

48 pedigrees of families with PINK1 mutations (AR)

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

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

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

52 An Exception !

53 A) novel homozygous nonsense PINK1 mutation in exon 3(C99A) leading to a loss of kinase domain of the PINK1 protein (Tyr258Stop).

54 B: A novel heterozygous missense mutation in the kinase domain of exon 4 (G62A) leading to an amino acid substitution (Ala280Thr).

55 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: )