title: Ageing enhances alpha-synuclein, ubiquitin and endoplasmic reticular stress protein expression in the nigral neurons of Asian Indians.
abstract: Accumulating evidences suggest that dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc) during ageing and in Parkinson's disease (PD) is linked to neurodegenerative changes like exponential increase in alpha-synuclein expression and protein misfolding. Lewy body formation is also a quintessential observation in neurodegeneration and PD. In experimental models of PD, GRP78 a neuroprotective endoplasmic reticulum (ER) chaperone protein targets misfolded proteins for degradation and prevents release of caspase12 from the ER. Release of active caspase12 and its translocation to the nucleus induces ER mediated apoptosis. The effect of ageing on these proteins in human nigra is not known. We evaluated alpha-synuclein, caspase12, GRP78 and ubiquitin expression in the SNpc of Asian Indians, using immunohistochemistry and stereology. The number of alpha-synuclein and caspase12 immunoreactive neurons increased gradually with age whereas the number of GRP78-labeled neurons remained stable. In contrast, GRP78 protein expression was significantly upregulated with age, while alpha-synuclein and caspase12 increased slightly. An increase in the size and numbers of marinesco bodies was prominent after the sixth decade. The mild increase in alpha-synuclein expression and occurrence of marinesco bodies suggests ageing induced protein misfolding and GRP78 upregulation indicates presence of ER stress. The logarithmic upregulation of GRP78 could even be an indicator of neuroprotective or neuromodulatory response of ER to protein misfolding and initiation of unfolded protein response pathway. Since dopaminergic neurons are preserved in ageing Asian Indians, our study possibly signifies better proteasomal or ER response and partially explains the lower prevalence of PD in them.
authors.affiliation: Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Bangalore, India. alladiphalguni@yahoo.com
authors.forename: Phalguni Anand
authors.initials: PA
authors.lastname: Alladi
authors.forename: Anita
authors.initials: A
authors.lastname: Mahadevan
authors.forename: K
authors.initials: K
authors.lastname: Vijayalakshmi
authors.forename: Uday
authors.initials: U
authors.lastname: Muthane
authors.forename: S K
authors.initials: SK
authors.lastname: Shankar
authors.forename: T R
authors.initials: TR
authors.lastname: Raju
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D044466:Asian People; D015153:Blotting, Western; D053454:Caspase 12 / Q000096:biosynthesis; D002648:Child; D002675:Child, Preschool; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007194:India; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008636:Mesencephalon / Q000378:metabolism; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D011247:Pregnancy; D013378:Substantia Nigra / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D025801:Ubiquitin / Q000096:biosynthesis*; D055815:Young Adult; D051844:alpha-Synuclein / Q000096:biosynthesis*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D025801:Ubiquitin; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; D053454:Caspase 12