Abstract:
Neurodegenerative disorders cause irreversible damage to the neurons and adversely
affect the quality of life. Protein misfolding and their aggregation in specific parts of the
brain, mitochondrial dysfunction, calcium load, proteolytic stress, and oxidative stress
are among the causes of neurodegenerative disorders. In addition, altered metabolism
has been associated with neurodegeneration as evidenced by reductions in glutamine
and alanine in transient global amnesia patients, higher homocysteine-cysteine disulfide,
and lower methionine decline in serum urea have been observed in Alzheimer’s disease
patients. Neurodegeneration thus appears to be a culmination of altered metabolism.
The study’s objective is to analyze various attributes like composition, physical properties
of the protein, and factors like selectional and mutational forces, influencing codon
usage preferences in a panel of genes involved directly or indirectly in metabolism and
contributing to neurodegeneration. Various parameters, including gene composition,
dinucleotide analysis, Relative synonymous codon usage (RSCU), Codon adaptation
index (CAI), neutrality and parity plots, and different protein indices, were computed and
analyzed to determine the codon usage pattern and factors affecting it. The correlation
of intrinsic protein properties such as the grand average of hydropathicity index (GRAVY),
isoelectric point, hydrophobicity, and acidic, basic, and neutral amino acid content has
been found to influence codon usage. In genes up to 800 amino acids long, the GC3
content was highly variable, while GC12 content was relatively constant. An optimum
CpG content is present in genes to maintain a high expression level as required for genes
involved in metabolism. Also observed was a low codon usage bias with a higher protein
expression level. Compositional parameters and nucleotides at the second position of
codons played essential roles in explaining the extent of bias. Overall analysis indicated
that the dominance of selection pressure and compositional constraints and mutational
forces shape codon usage.
