Clinical implications from proteomic studies in neurodegenerative diseases: lessons from mitochondrial proteins

ABSTRACT

Mitochondria play a key role in eukaryotic cells, being mediators of energy, biosynthetic and regulatory requirements of these cells. Emerging proteomics techniques have allowed scientists to obtain the differentially expressed proteome or the proteomic redox status in mitochondria. This has unmasked the diversity of proteins with respect to subcellular location, expression and interactions. Mitochondria have become a research ‘hot spot’ in subcellular proteomics, leading to identification of candidate clinical targets in neurodegenerative diseases in which mitochondria are known to play pathological roles. The extensive efforts to rapidly obtain differentially expressed proteomes and unravel the redox proteomic status in mitochondria have yielded clinical insights into the neuropathological mechanisms of disease, identification of disease early stage and evaluation of disease progression. Although current technical limitations hamper full exploitation of the mitochondrial proteome in neurosciences, future advances are predicted to provide identification of specific therapeutic targets for neurodegenerative disorders.

KEYWORDS:

• Proteomics
• redox proteomics
• mitochondria
• Alzheimer disease
• Parkinson disease
• neurodegeneration
• clinical biomarkers

Acknowledgment

This work was supported in part by the National Institutes of Health [NS094891] to D.A. Butterfield.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• Neurodegenerative disorders such as AD and PD are the major cause of dementia worldwide. The etiologies of these disorders remain unclear.

• Mitochondrial activities are known to play a role in the pathogenesis of these disorders, as both morphological and functional impairments of mitochondria are associated with these disorders.

• Mitochondrial proteins display specific features, and recent advances in proteomics have provided new tools to detect and identify mitochondrial proteins and confirm their mitochondrial localization.

• Due to the identified role of mitochondria in mediating neurodegeneration, extensive proteomic studies have been performed in brain of subjects with neurodegenerative disorders and animal models thereof, leading to the identification of many targets of protein dysregulation and oxidation.

• Integration of mitochondrial proteomics data with clinical information has provided important clues into the pathological events mediating neurodegeneration at molecular levels. These advances make the mitochondrial proteome an ideal target of studies with clinical implications in AD, PD, DS, and other neurodegenerative disorders.

• Current technical limitations hamper exploiting the mitochondrial proteome in neurosciences. Strong efforts are needed to overcome limitations with respect to mitochondrial purification, mitochondrial proteome coverage, and mitochondrial proteome database availability.

• Seminal findings on mitochondrial proteins of peripheral cells have demonstrated that mitochondrial proteins could conceivably be part of a panel of potential biomarkers of disease. However, diagnostic power, sensitivity, and reproducibility necessary for widespread use in a clinical setting are still lagging.