Iycee Charles de Gaulle Summary Creutzfeldt Jacob Disease Neurodegenerative Disorder Biology Essay

Creutzfeldt Jacob Disease Neurodegenerative Disorder Biology Essay

Several surveies shows that PrPc is a glycoprotein that is anchored to the cell surface by GPI ( GlycosylInositolPhasphatidyl ) and is involved in the conformational transition into PrPsc. Therefore, aiming transition of PrPc into PrPsc may be curative for the prion disease ( Carmen Krammer ) .

There are four countries identified as a curative marks for the intervention of Creutzfeldt Jacob disease in peculiar discrepancy Creutzfeldt Jacob disease ( vCJD ) .Batch of chemical compounds such as polyanionic compounds, polycationic compounds, starchlike binding compounds, tetra cyclic compounds were employed to cut down the PrPsc formation. These compounds can protract the incubation periods of the disease ( Suchiro sakaguchi ) .Anti prion chemical compounds have a limited consequence on the disease due to these molecules unable to traverse the blood encephalon barrier ( BBB ) . Due to this restriction immunotherapeutics such as anti PrP antibodies were developed to handle the disease.

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!

order now

Mechanism of antibody mediated prion inactivation:

In the seeding theoretical account ( figure — — ) , it was believed to be direct interaction between PrPSC templet and PrPC consequences in the formation of infective prions. Anti prion antibodies bind to the PrPC C-terminal portion ( residues 144-156 ) and suppress the formation of PrPSC. Anti PrP antibodies specifically adhere to the PrPC and its cellular receptors to bock or modify the interaction of PrPC with PrPSC.

Peptides with aminic acerb sequence of PrP ( 106-141 ) inhibit the transition in cell free system. ?-breaker peptides ( Peptides with PrP 115-122 ) can change by reversal the convertion of PrPSC and diminish the ?-sheet portion of the PrPSC to do it more susceptible to proteolysis.

Figure 1.

Mechanisms of antibody-mediated prion


Possible mechanism of prion inactivation by anti prion antibody. A ) Conversion of PrPC ( squares ) to PrPSc ( trigons ) harmonizing to the seeding theoretical account is shown to happen at the plasma membrane and/or endocytic cysts.

B ) Antibodies recognizing PrPC and PrPSc ( shown in thin line Y-shaped symbol ) interfere with the PrPC-PrPSc interaction. C ) Alternatively, antibody adhering sequesters PrPC and prevents itfrom reaching PrPSc. D ) Other mechanism of PrPSc suppression include specific binding of antibodies ( shown in bold line Y-shaped symbol ) against PrPSc ( 1 ) , antibody intervention with the binding of PrPC and its cellular receptor ( s ) ( 2 ) , or the binding of monovalent antibody fragments to PrPC ( 3 ) . For inside informations see text

Anti PrP antibodies:

Recently anti PrP antibodies employed to handle the disease in add-on to the chemical compounds. PrP specific antibody fragments can bring around the inveterate septic N2a cells ( suehiro sakaguchi ) .

Peretz et al treated the inveterate septic N2a cells with D13, D18, R1, R2, R72 and E49. They showed that D13 and D18 can cut down the PrPSC degrees in dosage dependent mode. Anti PrP activity is independent to each other due to the loosely located PrP multiple sites such as D18, D12, R2 and R1 specifically recognizes residues mediate 132-156, 95-103, 225-231, 220-231.Anti PrP antibodiesResiduesActivity3F4, 13A5 and Polyclonnal antibody ( W3 )109-112, 138-165, 219-232.Disturbs the interaction between PrPC and PrPSC.31C6, 110, 72 ( McAb ) and 44B1.143-149, 59-65 and 83-89 in the octapeptide part.PrPC internalization.

SAF34, SAF61144-152Octapeptide part3S9, 2H9 141-161 and 151-221 cut down PrPSC degrees.

Anti LRP/LR antibodies therapy:

Laminin receptor ( LRP/LR ) is a PrPC cell surface receptor. It is straight interact between PrP residues 144-179 and it is involved in the PrPSC formation. Leucht et Al showed that W3 ( LRP/LR specific polyclonal antibody ) competes with the recombinant PrP when adhering to the LRP/LR. ScFv antibodies have developed in recent times against specific antigenic determinants of PrPC.

The antigenic determinant of LRP for S18 located inside of the excess cellular sphere of LRP ( 272-280 ) . PrPSC degrees have been reduced ( about 40 % in lien ) when the prion infected mice treated with ScFv S18 when compared to the C9 and PBS as shown in the figure ____ . It is clearly indicated that ScFv S18 reduces the PrPSC extension by interrupting the interaction between PrP/LRP. However frequent high doses of ScFv S18 need to handle the disease due to the short half life of antibody.Figure: Epitope function of ScFv s18. ( a ) Membranes embracing the huLRP sequence were hybridized with S18. The sequence of the peptides detected and the amino acid places are indicated.

( B ) Schematic representation of LRP. The following binding sites are indicated: direct adhering site to PrP ( aa 161-179 ) ( Hundt et al. , 2001 ) , a suggested indirect HSPG-dependent binding sphere for PrP ( aa 180-285 ) ( Hundt et al. , 2001 ) , scFvS18 recognizes the antigenic determinant aa 272-280.Figure: Spleen analysis of mice inoculated with prions after intraperitoneal intervention with PBS, scFvC9 or scFvS18. Each group consists of six animate beings. ( a ) Analysis of PrPSc degrees ( after PK digestion ) in the lien has been performed 90 yearss after scrapie vaccination by western blotting. Shown are the PrPSc degrees of three mice of each group injected with PBS, C9 and S18, severally.

( B ) Densitometric measurings of western smudges from six liens per group revealed a decrease of the PrPSc degree by 40 % in the scFv S18 treated group compared to the PBS treated group, for which the PrPSc degree was set to 100 %

Direct injection of Anti PrP antibodies into encephalon:

White et Al showed that intraperitoneal injection of Two anti PrP antibodies such as ICSM18 and ICSM 35 protected the mice from RML prions peripherally but does non demo consequence in the encephalon tissue. This is likely because of inability of antibodies to traverse the blood encephalon barrier ( BBB ) . Direct extract of 3S9 monoclonal antibody into the right ventricle of the prion infected mice consequences in reduces PrPSC degrees after 8 hebdomads but does non demo consequence after 13 hebdomads ( sakaguchi ) .

Song et Al showed no important difference of protraction or marginally prolong the endurance times when the Chandler prion infected mice treated with 31C6. It is effectual against Chandler prion at 60, 90 and 120 yearss whereas no protraction with 31C6 when the mice infected with Obihiro strain. One job associated with the CNS bringing of anti PrP antibodies is toxicity. Cross associating between PrP and some specific antibodies ( bivalent ) promotes neural cell programmed cell death.

Virus vector mediated cistron bringing:

Antibodies are supermolecules that do non traverse the blood encephalon barrier ( BBB ) . Therefore, molecular size decrease ( without cut downing anti prion activity ) is really good for intervention such as monovalent individual concatenation variable fragments ( ScFv ) .

Recently, it is reported that adeno associated virus vector is used to present the anti PrP ScFv into the cardinal nervous system. Recombinant ScFv D18 has the ability to protract the incubation periods of the disease. PrP specific ScFvs have alone binding belongingss that include ScFv 3.4, ScFv 6.

4, ScFv 6.6 and ScFv D18. ScFv D18 has shown to be really effectual to protract the incubation periods when these antibodies are injected into the different parts of the encephalon, indicates that anti PrP ScFv inhibits the formation of PrPSC in the encephalon.Figure: Central nervous system ( CNS ) look of recombinant adeno-associated vector type 2 ( rAAV2 ) single-chain fragment variable ( scFv ) delays oncoming of prion disease.

( B ) Rotarod latencies from mice administered rAAV2 scFv D18 demonstrate improved public presentation compared to the other groups ; ( degree Celsius ) Clinical evaluation informations show that the oncoming of marks of disease was delayed in mice administered rAAV2 scFvD18. Maximal clinical evaluation mark achieved instantly anterior to animate beings making moribund position and sacrificed.

Role of blood encephalon barrier and the agents that can traverse blood encephalon barrier:

Blood encephalon barrier separates the blood from the cerebrospinal fluid and it restricts the entry of supermolecules such as drugs into the encephalon except that are little and lipophillic. The chief job in the therapy of creutzfeldt Jacob disease is inability of supermolecules such as chemical compound and antibodies to traverse the blood encephalon barrier. Non peptide agents capable of identify a specific signifier of protein or construction related to the neurological conditions such as prions in catching spongiform brain disorder. Renee Wegrzyn developed a promising attack of utilizing pyrene to present the curative agents across the blood encephalon barrier. When the pyrene conjugated to the non peptide curative agent, it increases the permeableness of the non peptide curative agent across the blood encephalon barrier.

Renee Wegrzyn et Al administered non peptide curative agent along with the pyrene ( conjugate ) to the mice intranasally ( 10µl liquid with 0.1-2.0 mg/ml, interval period 30 min ) and they found the presence of the conjugate in the encephalon of transgenic mice indicated that it can traverse the blood encephalon barrier.