Sandbox Reserved 938: Difference between revisions

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In part it makes the perfect sense - namely secretion of proteins is a very demanding procedure and the total amount of proteins that pancreas needs to produce and secrete is humongous. This means that the secretory cells have a much higher basal stress level than non-secreting cells. The more proteins are produced the higher the chance and also absolute amount of misfolded and/or unfolded proteins amassed that needs to be dealt with by the intracellular machinery. If now further damage is caused to these reparatory cascades the higher the chance for the cell to reach a point of no return and the UPR becoming too overwhelming and thus the cell goes into apoptosis. As expected thus, Lindahl et al. show the increased amount of TUNEL-positive pancreatic beta cells in MANF knock-out animals, confirming that eventually, beta cells undergo programmed cell death in response to increased ER-stress.

However, MANF was discovered as a neurotrophic factor and it's ability to protect neurons in different lesion models is remarkable and cannot simply be explained by any structural or functional features that we known of to this date. Furthermore, in 'Drosophila melanogaster'

However, MANF was discovered as a neurotrophic factor and it's ability to protect neurons in different lesion models is remarkable and cannot simply be explained by any structural or functional features that we known of to this date. Furthermore, in Drosophila melanogaster there are no two different CDNF and MANF proteins, is just one homologue, called DmMANF. The knock-out flies of that die due to a very specific developmental defect in the dopaminergic system in the central nervous system (Palgi et al., 2009). One would thus expect to see a more brain-related phenotype also in other organisms, but that does not seem to be the case at least for mice.

That would, in my opinion, argue for the lack of knowledge regarding the unstructured regions of the MANF protein, further covered in the next chapter.

==Conclusions and future perspectives==

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7. Mizobuchi N, Hoseki J, Kubota H, Toyokuni S, Nozaki J, Naitoh M, Koizumi A, Nagata K. ARMET is a soluble ER protein induced by the unfolded protein response via ERSE-II element. Cell Structure and Function, 2007.

8. Parkash V, Lindholm P, Peränen J, Kalkkinen N, Oksanen E, Saarma M, Leppänen VM, Goldman A. The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional, Protein Engineering, Design and Selection, 2009.

8. Palgi M, Lindström R, Peränen J, Piepponen TP, Saarma M, Heino TI. Evidence that DmMANF is an invertebrate neurotrophic factor supporting dopaminergic neurons, PNAS, 2009.

9. Parkash V, Lindholm P, Peränen J, Kalkkinen N, Oksanen E, Saarma M, Leppänen VM, Goldman A. The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional, Protein Engineering, Design and Selection, 2009.

9. Voutilainen MH, Bäck S, Pörsti E, Toppinen L, Lindgren L, Lindholm P, Peränen J, Saarma M and Tuominen RK. Mesencephalic Astrocyte-Derived Neurotrophic Factor Is Neurorestorative in Rat Model of Parkinson's Disease, Journal of Neuroscience, 2009.

10. Voutilainen MH, Bäck S, Pörsti E, Toppinen L, Lindgren L, Lindholm P, Peränen J, Saarma M and Tuominen RK. Mesencephalic Astrocyte-Derived Neurotrophic Factor Is Neurorestorative in Rat Model of Parkinson's Disease, Journal of Neuroscience, 2009.

Sandbox Reserved 938: Difference between revisions

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@@ Line 30: / Line 30: @@
 In part it makes the perfect sense - namely secretion of proteins is a very demanding procedure and the total amount of proteins that pancreas needs to produce and secrete is humongous. This means that the secretory cells have a much higher basal stress level than non-secreting cells. The more proteins are produced the higher the chance and also absolute amount of misfolded and/or unfolded proteins amassed that needs to be dealt with by the intracellular machinery. If now further damage is caused to these reparatory cascades the higher the chance for the cell to reach a point of no return and the UPR becoming too overwhelming and thus the cell goes into apoptosis. As expected thus, Lindahl et al. show the increased amount of TUNEL-positive pancreatic beta cells in MANF knock-out animals, confirming that eventually, beta cells undergo programmed cell death in response to increased ER-stress.
-However, MANF was discovered as a neurotrophic factor and it's ability to protect neurons in different lesion models is remarkable and cannot simply be explained by any structural or functional features that we known of to this date. Furthermore, in 'Drosophila melanogaster'
+However, MANF was discovered as a neurotrophic factor and it's ability to protect neurons in different lesion models is remarkable and cannot simply be explained by any structural or functional features that we known of to this date. Furthermore, in Drosophila melanogaster there are no two different CDNF and MANF proteins, is just one homologue, called DmMANF. The knock-out flies of that die due to a very specific developmental defect in the dopaminergic system in the central nervous system (Palgi et al., 2009). One would thus expect to see a more brain-related phenotype also in other organisms, but that does not seem to be the case at least for mice.
+That would, in my opinion, argue for the lack of knowledge regarding the unstructured regions of the MANF protein, further covered in the next chapter.
 ==Conclusions and future perspectives==
@@ Line 58: / Line 60: @@
 . Mizobuchi N, Hoseki J, Kubota H, Toyokuni S, Nozaki J, Naitoh M, Koizumi A, Nagata K. ARMET is a soluble ER protein induced by the unfolded protein response via ERSE-II element. Cell Structure and Function, 2007.
-. Parkash V, Lindholm P, Peränen J, Kalkkinen N, Oksanen E, Saarma M, Leppänen VM, Goldman A. The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional, Protein Engineering, Design and Selection, 2009.
+. Palgi M, Lindström R, Peränen J, Piepponen TP, Saarma M, Heino TI. Evidence that DmMANF is an invertebrate neurotrophic factor supporting dopaminergic neurons, PNAS, 2009.
+. Parkash V, Lindholm P, Peränen J, Kalkkinen N, Oksanen E, Saarma M, Leppänen VM, Goldman A. The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional, Protein Engineering, Design and Selection, 2009.
 . Voutilainen MH, Bäck S, Pörsti E, Toppinen L, Lindgren L, Lindholm P, Peränen J, Saarma M and Tuominen RK. Mesencephalic Astrocyte-Derived Neurotrophic Factor Is Neurorestorative in Rat Model of Parkinson's Disease, Journal of Neuroscience, 2009.