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The neurodegenerative link to the nuclear pore complex and nucleocytoplasmic transport 

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The Nuclear Pore Hypothesis of Neurodegeneration

There is mounting scientific evidence suggesting that defects in the nuclear pore complex and nucleocytoplasmic transport mechanisms underly neurodegenerative disease progression.

Impairments with nuclear transport receptors have been shown to impede multiple 'molecular highways' across the pore, reduce nucleocytoplasmic transport of critical cargo, and ultimately result in whole-body or tissue-specific diseases.

 

The specific type of neurodegeneration generally depends on three factors:

  • the type of nucleoporins (NUPs) affected

  • the type of cargo the NUPs are responsible for trafficking through the cell

  • the level of dependence that the cell or tissue type's have on the trafficked cargo

The link between the nuclear pore complex and disease is important because of the critical role the nuclear pore complex has in the exchange of crucial information in the cell. However, now this link is receiving increasing focus in relation to neurodegenerative diseases.

Our CSO has authored the paper on the Nuclear Pore Hypothesis of Neurodegeneration, read more here.

The Nuclear Pore Hypothesis of Neurodegeneration

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A. N. Coyne and J. D. Rothstein, “Nuclear pore complexes — a doorway to neural injury in neurodegeneration,” Nature Reviews Neurology, vol. 18, no. 6, pp. 348–362, 2022.

Enter the O-GlcNAcylation pathway

O-GlcNAcylation is a post-translational modification that regulates fundamental cellular processes, and is mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA).

O-GlcNAc modification is highly abundant in the protein components of the nuclear pore complex called nucleoporins (NUPs).

Loss of O-GlcNAc by the inhibition or knock-out of OGT leads to the loss of critical NUPs, which results in the breakdown of the nuclear pore complexes selective permeability barrier. 

 

Depleted O-GlcNAc has been shown to cause the aggregation of many neurodegenerative disease proteins such as tau, α-synuclein, superoxide dismutase and neurofilament proteins - effectively contributing to the 'molecular traffic jams'. 

Therefore, inhibition of OGA, leading to the increase in O-GlcNAc levels, may result in the preventing and/or alleviating the aggregation of toxic proteins that are common indicators in neurodegenerative diseases. 

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J. C. Grima, J. G. et al, “Mutant huntingtin disrupts the Nuclear Pore Complex,” Neuron, vol. 94, no. 1, 2017.

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Image by Josh Appel

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