title: Damaged proteins bearing L-isoaspartyl residues and aging: a dynamic equilibrium between generation of isomerized forms and repair by PIMT.
abstract: Proteins are susceptible to numerous non-enzymatic post-translational modifications which occur both during normal aging and in neurodegenerative states. For instance, formation of abnormal L-isoaspartyl residues arising from both the deamidation of L-asparaginyl residues and the isomerization of L-aspartyl residues is a frequent chemical modification that affects proteins. The formation of L- isoaspartyl residues in proteins alters their three-dimensional structure leading usually to a loss of function. Notably, accumulation of isomerized proteins could contribute to metabolic dysfunctions in neuronal cells during aging reducing cognitive functions in elderly patients and would eventually promote the development of neurodegenerative diseases. The protein L-isoaspartyl (D-aspartyl) methyltransferase (PIMT) is an enzyme that recognizes and repairs the abnormal L-isoaspartyl residues in proteins. Its expression appears to decline during aging which could partially explain the build up of damaged proteins in old age. In this review, we summarize recent findings, based mostly on proteomic data, regarding the formation and accumulation of proteins bearing atypical L-isoaspartyl residues as well as PIMT functions during normal aging and in some neurodegenerative diseases. The emphasis is on possible molecular mechanisms controlling PIMT expression and the ability of PIMT to repair isomerized substrates during aging. Investigation of processes regulating age-related accumulation of isomerized proteins is a promising avenue to a better understanding of aging at the protein level.
authors.affiliation: Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montréal, Québec, Canada, H3C 3P8. desrosiers.r@uqam.ca
authors.forename: Richard R
authors.initials: RR
authors.lastname: Desrosiers
authors.forename: Irvens
authors.initials: I
authors.lastname: Fanélus
mesh_terms: D000375:Aging / Q000378:metabolism*; D006801:Humans; D026581:Isoaspartic Acid / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000502:physiology; D011506:Proteins / Q000378:metabolism*
chemical_list: D026581:Isoaspartic Acid; D011506:Proteins; C435725:PCMT1 protein, human; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase