Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Frontotemporal Lobar Degeneration (FTLD) is a complex group of neurodegenerative disorders.
• It presents with distinct clinical syndromes: behavioral variant FTD (bvFTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA).
• FTLD is characterized by heterogeneous pathologies involving tau, TDP-43, and FUS proteins, and genetic mutations in genes like MAPT, GRN, and C9orf72.

Purpose of the Study:

• To elucidate the complex relationships between clinical presentations, proteinopathies, and genetic factors in FTLD.
• To explore the potential role of cellular protein degradation pathways in FTLD pathogenesis.
• To understand how protein aggregate spread influences FTLD phenotypes and progression.

Main Methods:

• Review and synthesis of existing clinical, pathological, and genetic data on FTLD and related disorders.
• Analysis of the known functions of key proteins (tau, TDP-43, FUS) and their associated genes in cellular processes.
• Correlation of specific protein aggregates and genetic mutations with clinical syndromes and disease progression patterns.

Main Results:

• SD and PNFA show strong links to TDP-43 proteinopathies and specific genetic factors.
• bvFTD exhibits more complex overlaps in protein and genetic involvement.
• Amyotrophic Lateral Sclerosis (ALS) cases with FTLD show TDP-43 pathology, with C9orf72 expansions in familial forms.
• TDP-43 and FUS mutations are linked to RNA metabolism dysfunction in ALS, while GRN and C9orf72 relate to protein degradation.

Conclusions:

• FTLD may arise from failures in the lysosomal/proteasomal degradation systems, leading to the accumulation of neurotoxic protein aggregates.
• The spread of these aggregates along specific neural pathways likely dictates the diverse clinical phenotypes and disease progression observed in FTLD.
• Understanding these pathways offers insights into potential therapeutic targets for FTLD and related neurodegenerative diseases.