Mutation Lrrk2 Parkinson

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un espoir pour traiter la maladie de parkinson

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Mutation Lrrk2 Parkinson

  1. 1. 1 NEW MODEL TO STUDY PARKINSONS DISEASEElise VillersLaurent Magnies
  2. 2. Introduction2 An estimated 4 million the number of people affected by Parkinsons disease Parkinsons disease usually starts between 55 and 65 With the ageing of the world population, the importance of Parkinsons disease as a public health issue expected to increase The number of people with Parkinsons disease worldwide will double in 25 years
  3. 3. Parkinson’s disease3A degenerative disorder of the central nervoussystem. The motor symptoms of Parkinsonsdisease result from the progressive loss ofdopamine-generating cells in the substantia nigra,a region of the midbrain Clinic symptoms are movement-related: Shaking Rigidity Bradykinesia Difficulty with walking and gait In the advanced stages of the disease: cognitive and behavioural problems dementia
  4. 4. Genetic contribution?4 Purely idiopathic In 1900, Gowers reported that 15% of patients had a family history A genetic contribution is suspected for a long time Genetic factors involved in 10% of cases Difficult to reproduce the disease in animals due to an incomplete understanding Recently, it was found that mutations of the gene coding for LRRK2, brain enzyme, was the prevalent genetic cause of PD
  5. 5. LRRK2: Leucine Rich Repeat Kinase 2 gene 5 Chromosome 12 51 exons  encode a 2,527 AA protein Belong to ROCO (Ras-GTPase) protein family wich is involved in diverse cellular processes: - Regulation of cell polarity - Chemotaxis - Cytokinesis - Cytoskeletal rearrangements - Programmed cell deathAvner Thaler. The LRRK2 G2019S mutation as the cause of Parkinson’s disease in Ashkenazi Jews. J Neural Transm (2009)116:1473–1482.Suzanne Lesage, LRRK2, gène majeurde la maladie de Parkinson dans les pays du Maghreb. M/S : médecine sciences, vol. 22, n°
  6. 6. What do we know about LRRK2? 6  Contain many domains:  LRRK2 distribution coincides with brain areas most affected by PD  Mutations in LRRK2 are the most common cause of genetic Parkinsonism  Dominant mode of inheritance with G2019S  30 mutations in LRRK2 and 5 pathogensAvner Thaler. The LRRK2 G2019S mutation as the cause of Parkinson’s disease in Ashkenazi Jews. J Neural Transm (2009) 116:14731482
  7. 7. 7
  8. 8. Focus on G2019S: the most8 common mutation GLY  SER amino acid 2,019 MAPKKK domain To protect the active site To regulate kinase activity as an anchor for the Mg ion
  9. 9. Focus on G2019S: the most 9 common mutation Conformationnal change that: - Increase Kinase activity - Enhance autophosphorylation - Cause neuronal cells’ death=> dopamineAvner Thaler. The LRRK2 G2019S mutation as the cause of Parkinson’s disease in Ashkenazi Jews. J Neural Transm (2009)
  10. 10. Journal of neuroscience : A Rat Model of Progressive Nigral Neurodegeneration 10 To introduce the enzyme mutated LRRK2 in the cerebral hemisphere of a rat  To reproduce the robust nigral neurodegeneration To optimize an adenoviral vector to transport, in the nigrostriatal system of adult rats, the DNA encoding the mutated enzyme Difficult to design a vector due to the complexity and the size of the LRRK2Journal of neuroscience : A Rat Model of Progressive Nigral
  11. 11. Technics and Results 11 Recombinant Ad vectors were injected in the striatum we observed a widespread distribution of vector around the injection sites, resulting in efficient transport and good expression in nigral subtance High-magnification photomicrographs of anti-FLAG immunostainingsJournal of neuroscience : A Rat Model of Progressive Nigral
  12. 12. Technics and Results 12 TH: dopaminergic marker No cell loss is detected in rad-WT- LRRK2-injected groups Overexpression of LRRK2 G2019S causes a progressive loss of TH- positive dopaminergic neurons Photomicrographs showing the loss of TH+Journal of neuroscience : A Rat Model of Progressive Nigral
  13. 13. Next, we explored the alterations associated with neuronal degeneration due to G2019S LRRK2 overexpression Immunostaining  Abnormal hyperphosphorylation of tau protein in neurons dystrophies with the mutation G2019S. Adenoviral vectors provide an efficient answer to the size constraints of the LRRK2 coding sequence (7.6 kb) and represent highly flexible tools for the study of 13 mutant LRRK2 pathogenesis PD of adult ratsJournal of neuroscience : A Rat Model of Progressive Nigral
  14. 14. Worldwide frequency 14Suzanne Lesage, LRRK2, gène majeurde la maladie de Parkinson dans les pays du Maghreb. M/S : médecine sciences, vol. 22, n°5, 2006, p. 470-471.
  15. 15. A study in Cantabria 15 18 probands reported 367 having 1st or 2nd 32 proven carriers degree relative PD patients affected by PD 13 9 proven carriers 126 Clinically affected Tested at-risk relatives 113 47 proven carriers Clinically unaffectedMarı´a Sierra. High Frequency and Reduced Penetrance of LRRK2 G2019S Mutation Among Parkinson’s Disease Patients inCantabria (Spain). Service of Neurology, University Hospital ‘‘Marque´ s de Valdecilla,’’ University of Cantabria (UC). Movement
  16. 16. Discussion 16  Homogeneous population coming from a small geographical area and isolated =>To extrapolate to the population and providing an accurate genetic counseling in a local context BUT extrapolate to others seem improbableMarı´a Sierra. High Frequency and Reduced Penetrance of LRRK2 G2019S Mutation Among Parkinson’s Disease Patients in Cantabria(Spain). Service of Neurology, University Hospital ‘‘Marque´ s de Valdecilla,’’ University of Cantabria (UC). Movement Disorders, Vol. 26
  17. 17. LRRK2: to test or not to test?17 Genetic testing for the G2019S mutation might enable early detection and confirmation of PD : Improving the accuracy of diagnosis Rigorous follow- up in patients which may delay or minimize complications of the disease To test neuroprotective strategies as they become available Cause and no consequences Aiding in the understanding of the pathogenesis and clinics results But These targets are all still under research Predictive test of the G2019S mutation is not currently recommended, partly due to the lack of current neuroprotective therapies.
  18. 18. LRRK2 : enzyme catalytic Therapeutic target Therapeutic target for the treatment of Parkinsons disease To identify neuroprotective strategies to slow or stop progression of the disease Development of new pharmaceuticals that inhibit the hyperactivity of enzyme18

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