Experimental Disease-Modifying Agents for Frontotemporal Lobar Degeneration

Abstract

Frontotemporal dementia is a clinically, genetically and pathologically heterogeneous neurodegenerative disorder, enclosing a wide range of different pathological entities, associated with the accumulation of proteins such as tau and TPD-43. Characterized by a high hereditability, mutations in three main genes, MAPT, GRN and C9orf72, can drive the neurodegenerative process. The connection between different genes and proteinopathies through specific mechanisms has shed light on the pathophysiology of the disease, leading to the identification of potential pharmacological targets. New experimental strategies are emerging, in both preclinical and clinical settings, which focus on small molecules rather than gene therapy. In this review, we provide an insight into the aberrant mechanisms leading to FTLD-related proteinopathies and discuss recent therapies with the potential to ameliorate neurodegeneration and disease progression.

Keywords: C9orf72; GRN; MAPT; TDP-43; frontotemporal dementia; frontotemporal lobar degeneration; tau; therapy.

Figure 1

Principal pathogenic steps toward tau-related neurodegeneration. Pathophysiological transformations leading to tau dysfunction. The related potential therapeutic strategies are reported in the boxes. Images created with BioRender.com

Figure 2

Aberrant TDP-43 biology in FTLD. Pathological model of TDP-43-associated neurodegeneration and the corresponding potential therapeutic approach (in blue boxes). Note the pathways involving C9Orf72 expansions and progranulin. Images created with BioRender.com.