Facebook PixelHow can we investigate the complexities of neurodegenerative disease?
Brainstorming
Brainstorming
Brainstorming session

How can we investigate the complexities of neurodegenerative disease?

How can we investigate the complexities of neurodegenerative disease?

Image credit: Stephanie Holst

By Stephanie Holst on Sep 09, 2020

[1] Duyckaerts, C., Delatour, B. & Potier, M. Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118, 5–36 (2009). https://doi.org/10.1007/s00401-009-0532-1

[2] Parsons MP, Kang R, Buren C, et al. Bidirectional control of postsynaptic density-95 (PSD-95) clustering by Huntingtin. J Biol Chem. 2014;289(6):3518-3528. doi:10.1074/jbc.M113.513945

[3] Guan, X.; Fierke, C. A. Understanding Protein Palmitoylation: Biological Significance and Enzymology. Science China Chemistry 2011, 54 (12), 1888–1897. https://doi.org/10.1007/s11426-011-4428-2.

[4] Resh, M. D. Covalent Lipid Modifications of Proteins. Current Biology 2013, 23 (10), R431–R435. https://doi.org/10.1016/j.cub.2013.04.024.

[5] Pizzarelli, R.; Griguoli, M.; Zacchi, P.; Petrini, E. M.; Barberis, A.; Cattaneo, A.; Cherubini, E. Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions. Neuroscience 2019. https://doi.org/10.1016/j.neuroscience.2019.07.036.

[6] Fukata, Y.; Fukata, M. Protein Palmitoylation in Neuronal Development and Synaptic Plasticity. Nature Reviews Neuroscience 2010, 11 (3), 161–175. https://doi.org/10.1038/nrn2788.

[7] Greaves, J.; Prescott, G. R.; Gorleku, O. A.; Chamberlain, L. H. The Fat Controller: Roles of Palmitoylation in Intracellular Protein Trafficking and Targeting to Membrane Microdomains (Review). Molecular Membrane Biology 2009, 26 (1–2), 67–79. https://doi.org/10.1080/09687680802620351.

Creative contributions

The isoaspartate modification is involved in Alzheimer’s disease pathology.

Thanks for starting this interesting brainstorming session. As we already know, toxic protein aggregates are a characteristic of neurodegenerative diseases, post-translational modifications can alter the protein shape and function, and so post-translational modifications could indeed promote protein aggregation and accelerate the progression of neurodegenerative disorders. [1] Various post-translational modifications like the isoaspartate modification, glycation, nitration, phosphorylation, and others have been linked to Alzheimer’s disease. [1] The isoaspartate modification is a non-enzymatic post-translational modification that spontaneously occurs as we age. The isoaspartate modification occurs when an aspartate residue becomes isomerized or when an asparagine residue becomes deaminated. [3] In regards to Alzheimer’s disease, isoaspartate modifications occur at the D1, D7, and D23 residues of amyloid-beta (Aβ). Studies have confirmed that these isoaspartate modifications promote the aggregation of Aβ and accelerate the formation of fibrillar aggregates, and thereby could be associated with the progression of Alzheimer's disease. [2, 3] References 1. Schaffert, Larissa-Nele, and Wayne G. Carter. "Do Post-Translational Modifications Influence Protein Aggregation in Neurodegenerative Diseases: A Systematic Review." Brain Sciences 10.4 (2020): 232. 2. Shimizu, Takahiko, et al. "Isoaspartate formation at position 23 of amyloid beta peptide enhanced fibril formation and deposited onto senile plaques and vascular amyloids in Alzheimer's disease." Journal of neuroscience research 70.3 (2002): 451-461. 3. Fossati, Silvia, et al. "Differential contribution of isoaspartate post-translational modifications to the fibrillization and toxic properties of amyloid β and the Asn23 Iowa mutation." Biochemical Journal 456.3 (2013): 347-360.

by Jamila Ahmed on Sep 11, 2020

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