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Review
. 2024 Aug 4;5(8):e674.
doi: 10.1002/mco2.674. eCollection 2024 Aug.

Protein modification in neurodegenerative diseases

Shahin Ramazi  1 , Maedeh Dadzadi  2 , Mona Darvazi  1 , Nasrin Seddigh  3 , Abdollah Allahverdi  1
Affiliations
Review

Protein modification in neurodegenerative diseases

Shahin Ramazi et al. MedComm (2020). .

Abstract

Posttranslational modifications play a crucial role in governing cellular functions and protein behavior. Researchers have implicated dysregulated posttranslational modifications in protein misfolding, which results in cytotoxicity, particularly in neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and Huntington disease. These aberrant posttranslational modifications cause proteins to gather in certain parts of the brain that are linked to the development of the diseases. This leads to neuronal dysfunction and the start of neurodegenerative disease symptoms. Cognitive decline and neurological impairments commonly manifest in neurodegenerative disease patients, underscoring the urgency of comprehending the posttranslational modifications' impact on protein function for targeted therapeutic interventions. This review elucidates the critical link between neurodegenerative diseases and specific posttranslational modifications, focusing on Tau, APP, α-synuclein, Huntingtin protein, Parkin, DJ-1, and Drp1. By delineating the prominent aberrant posttranslational modifications within Alzheimer disease, Parkinson disease, and Huntington disease, the review underscores the significance of understanding the interplay among these modifications. Emphasizing 10 key abnormal posttranslational modifications, this study aims to provide a comprehensive framework for investigating neurodegenerative diseases holistically. The insights presented herein shed light on potential therapeutic avenues aimed at modulating posttranslational modifications to mitigate protein aggregation and retard neurodegenerative disease progression.

Keywords: SUMOylation; immune system; neurodegenerative diseases; posttranslational modifications.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
The graphical abstract showcases the diversity of posttranslational modifications (PTMs) influencing protein structure and function. It features schematic representations of the following 10 prominent PTMs: phosphorylation (addition of phosphate groups), acetylation (addition of acetyl groups), methylation (addition of methyl groups), SUMOylation (attachment of SUMO proteins), ubiquitylation (attachment of ubiquitin molecules), succinylation (addition of succinyl groups), S‐nitrosylation (attachment of NO), ADP‐ribosylation (addition of ADP‐ribose groups), glycosylation (addition of sugar molecules), and palmitoylation (attachment of palmitate groups).
FIGURE 2
FIGURE 2
SUMOylation is a reversible modification in which SUMO is covalently attached to proteins through an enzymatic cascade involving three enzymes: an activating enzyme (E1), a conjugating enzyme (E2), and a ligating enzyme (E3). Ultimately, SUMO is removed by a sumo‐specific protease.
FIGURE 3
FIGURE 3
The SUMOylation of parkin triggers its own self‐ubiquitination and prompts it to move into the cell's nucleus. This process consequently reduces the pool of parkin accessible for mitochondrial recruitment. Parkin dysfunction disrupts normal mitochondrial biogenesis due to the accumulation of a specific protein called PARIS, which negatively regulates PGC‐1α expression. While SENP enhances the transcriptional activity of PGC‐1α by removing SUMO tags, the presence of SUMO and PSF inhibits PGC‐1α’s ability to activate genes. DJ‐1, associated with an early‐onset recessive condition, hampers the SUMOylation of PSF, leading to a reduction in the creation of new mitochondria. SENP, sentrin‐specific proteases; PSF, pyrimidine tract‐binding protein‐associated splicing factor.
FIGURE 4
FIGURE 4
Phosphorylation is a covalent modification that involves the addition of a phosphate group to serine, threonine, tyrosine, and histidine residues by kinase enzymes. Conversely, dephosphorylation, or the removal of a phosphate group, is an enzymatic reaction catalyzed by various phosphatases (PPs).
FIGURE 5
FIGURE 5
Acetylation is a reversible modification that is regulated by acetyltransferase enzymes. Acetyltransferases utilize acetyl CoA as a cofactor to add an acetyl group (COCH3) to the ε‐amino group of lysine side chains, while deacetylases remove acetyl groups from lysine side chains.
FIGURE 6
FIGURE 6
Ubiquitination is one type of reversible posttranslational modification (PTM) of proteins. Ubiquitin is covalently attached to proteins through a peptide bond between its C‐terminal glycine and the Nε lysine residues of target proteins. The process involves three enzymes: an activating enzyme (E1), a conjugating enzyme (E2), and an ubiquitin ligase (E3). Ubiquitin can be removed from the protein by deubiquitinating enzymes (DUBs).
FIGURE 7
FIGURE 7
Glycosylation is an enzymatically reversible covalent modification involving glycosyltransferases (GTs) and glycosidases. Glycosylation entails the addition of carbohydrate units to serine, threonine, asparagine, and tryptophan residues in proteins and lipoproteins. (A) N‐linked glycosylation involves the attachment of oligosaccharides to asparagine residues. (B) O‐linked glycosylation consists of adding a sugar to the hydroxyl group (OH) of serine or threonine residues.
FIGURE 8
FIGURE 8
Palmitoylation is the covalent attachment of fatty acids, like palmitic acid, to the cysteine residues of proteins. Palmitoyl‐CoA is attached to the target protein by palmitoyltransferases (PATs) and removed via acyl protein thioesterases (APTs).
FIGURE 9
FIGURE 9
Methylation, as a reversible modification, transfers the methyl group from the donor S‐adenosylmethionine (SAM) to target residues via methyltransferases, eliminating the methyl group by the demethylase enzymes.
FIGURE 10
FIGURE 10
ADP‐ribosylation involves the covalent attachment of one or more ADP‐ribose moieties from NAD+ to specific residues on target proteins, such as cysteine, arginine, glutamic acid, aspartic acid, and serine (x). This modification is catalyzed by a family of enzymes called ADP‐ribosyltransferases (ARTs). The ADP‐ribosylation of proteins is a reversible process, as specialized enzymes called ADP‐ribosylhydrolases can remove the ADP‐ribose moieties.
FIGURE 11
FIGURE 11
S‐nitrosylation is indeed a reversible modification involving the covalent interaction of a nitric oxide group (‐NO) with the thiol group of cysteine residues (‐S‐) on a target protein. This modification is catalyzed by nitrosylases and can be removed by denitrosylase enzymes.
FIGURE 12
FIGURE 12
Succinylation is a reversible modification that involves the transfer of a succinyl group (‐CO‐CH2‐CH2‐CO2H) via succinyl‐CoA to a lysine residue of a protein. Succinylases catalyze this modification, which can be removed by desuccinylase enzymes.
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