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How can we investigate the complexities of neurodegenerative disease?

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Stephanie Holst Sep 09, 2020

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Neurodegenerative diseases are a classification of diseases that can lead to movement and/or cognitive ailments due to the gradual degeneration and/or death of neurons. Since little is known about their pathology, how can we tackle the investigation of such complex diseases?

Alzheimer’s Disease (AD) diagnosis and pathology is generally divided into three main categories by lesions: accumulation (Aβ peptide and tau protein), loss, and those due to reactive processes such as inflammation and plasticity     . Whereas Huntington’s Disease (HD) is diagnosed by detection of the genetically modified huntington protein (mHTT) which is characterized by an N-terminal polyglutamine expansion     . While the pathology of HD is exhibited to the deficits in cellular and synaptic function due to mHTT, which eventually lead to cell death.

S-Palmitoylation is a reversible post-translational modification (PTM) in which a 16-carbon fatty acid chain covalently attaches to cysteine via a thioester bond        . Proteins that undergo such lipophilic PTMs have been observed to have an increased affinity for membranes thereby localizing proteins to membranes, as seen in the figure.

Gephyrin, an inhibitory scaffolding protein, has been shown accumulate and co-localizes with Aβplaques in AD    . Gephyrin is known to be palmitoylated at two sites and may not localize appropriately without palmitoylation.5 In mouse models, it was shown that a mutation of the palmitoylation site of mHTT can lead to decreased palmtoylation and increased formation of inclusion bodies by mHTT        .

Is it possible to study the expansive pathology of these complex diseases by also looking into decreased protein palmitoylation with disease progression? What other PTM’s seem to be affected during ND progression?

[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.

palmitoylation neurodegenerative disease

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

Jamila Sep 11, 2020

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.

How can we investigate the complexities of neurodegenerative disease?

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