The Need for Biomarkers in the ALS-FTD Spectrum: A Clinical Point of View on the Role of Proteomics

Abstract

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are severely debilitating and progressive neurodegenerative disorders. A distinctive pathological feature of several neurodegenerative diseases, including ALS and FTD, is the deposition of aberrant protein inclusions in neuronal cells, which leads to cellular dysfunction and neuronal damage and loss. Despite this, to date, the biological process behind developing these protein inclusions must be better clarified, making the development of disease-modifying treatment impossible until this is done. Proteomics is a powerful tool to characterize the expression, structure, functions, interactions, and modifications of proteins of tissue and biological fluid, including plasma, serum, and cerebrospinal fluid. This protein-profiling characterization aims to identify disease-specific protein alteration or specific pathology-based mechanisms which may be used as markers of these conditions. Our narrative review aims to highlight the need for biomarkers and the potential use of proteomics in clinical practice for ALS-FTD spectrum disorders, considering the emerging rationale in proteomics for new drug development. Certainly, new data will emerge in the near future in this regard and support clinicians in the development of personalized medicine.

Keywords: amyotrophic lateral sclerosis; biomarkers; frontotemporal dementia; neurodegenerative diseases; proteomics.

Figure 1

Clinical and pathological characteristics in the ALS–FTD spectrum. The figure represents the relative rate of protein deposits in the clinical subtypes. Most ALS patients present TDP-43 inclusions. SOD-1 alterations are typical in genetic ALS. TDP-43 is also associated with most svPPA cases and about 50% of bvFTD cases. The other most represented neuropathology substrate in bvFTD is represented by tau deposition, which also characterizes nfvPPA’s forms. ALS, ALS–FTD, and bvFTD are infrequently associated with FUS and other pathologies. Abbreviations: ALS, amyotrophic lateral sclerosis; bvFTD, behavioral variant FTD; FTD, frontotemporal dementia; FUS, RNA-binding protein FUS; nfvPPA, nonfluent variant primary progressive aphasia; SOD-1, superoxide dismutase type 1; svPPA, semantic variant primary progressive aphasia; TDP-43, transactive response DNA-binding protein 43.

Figure 2

The main factors explaining the variability in gene expression, RNA synthesis, transcription, and protein expression and function. DNA can express variable coding potential using alternative transcription start sites, modulating DNA methylation, and chromatin accessibility. Alternative splicing can occur at the transcriptional level, and post-transcriptional editing of RNA increases variability in protein expression. Lastly, localization, abundance, and post-translational modifications influence protein function, which can also be affected by how proteins interact.