Proteomic Study of Degenerative Protein Modifications in the Molecular Pathology of Neurodegeneration and Dementia

Abstract

Dementia is a major public health burden, and the World Health Organization has identified this disorder as a major public health priority. There are limited treatment options due to poor understanding of key mechanism of dementia pathogenesis. Dementia has been regarded as a proteinopathy in which alterations of brain protein structure and function are the key features of the disorder. Proteinopathy can be triggered by degenerative protein modifications (DPMs), misfolding, aggregation, and deposition of the malformed proteins. Despite the clinical significance of alteration in protein abundances, DPMs, protein misfolding, and aggregation, the molecular mechanism that promotes these changes remains inadequately understood, mostly due to technical challenges. Proteomic is a powerful, sensitive, and advanced tool to study the progressive brain tissue damage that critically dysregulates key enzymes, accumulates modified proteins, and causes protein misfolding and aggregation, resulting in cognitive decline and dementia. The proteomic profiling of protein abundances and correlating DPMs with protein misfolding and aggregation have potential to elucidate underlying molecular mechanism of the disease. This chapter summarizes the recent proteomic developments for studying brain proteome, DPMs, and protein aggregation mechanism that may lead to dementia. We attempted to correlate DPMs and its impact on protein aggregation and deposition in brain tissues.

Hypoxia-Induced Degenerative Protein Modifications Associated with Aging and Age-Associated Disorders

“…The clinical and experimental studies concluded that cerebrovascular disease and hypoxic-ischemic brain injury are the primary causes of cognitive impairment and dementia [29]. The progressive cycle of hypoxic-ischemic brain injury induces protein misfolding, aggregation and DPMs, leading to cognitive decline and dementia [15]. Further, the changes and posttranslational modification of proteins in response to chronic sustained and intermittent forms of hypoxia have been reviewed by Kumar and Klein [102].…”

“…The proteins undergo alterations by spontaneous non-enzymatic Degenerative Protein Modifications (DPMs) including oxidation, deamidation, carbamylation, carbonylation, glycation etc. The DPMs change protein charge state, hydrophobicity and threedimensional structure that influence functional activities and induce aggregation [9][10][11][12][13][14][15]. These protein modifications and accumulation of modified proteins are allied to aging and the development of age-associated pathologies like neurodegenerative diseases [10,16].…”