[TDP-43 proteinopathies: ALS and frontotemporal dementias]

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Context:

• Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) are primarily sporadic neurodegenerative diseases.
• Cytoplasmic ubiquitinated inclusions in neurons are the pathological hallmark for ALS, FTLD-U, and their combined form (FTLD-U/MND).
• The TAR DNA-binding protein of 43 kDa (TDP-43) was identified as the main component of these inclusions in 2006, defining TDP-43 proteinopathies.

Purpose:

• To investigate the role of TDP-43 in neurodegeneration within ALS and FTLD-U.
• To understand the pathological mechanisms involving TDP-43 mislocalization and potential loss-of-function or toxic gain-of-function.
• To explore the genetic basis of these diseases, particularly the link between TARDBP mutations and familial ALS.

Summary:

• TDP-43, a nuclear protein regulating gene expression, is found abnormally truncated, hyperphosphorylated, and mislocalized in affected neurons.
• The exact disease mechanism—whether it's loss of nuclear function or gain of toxic function—remains unclear.
• While TARDBP mutations are linked to autosomal-dominant familial ALS (ALS 10), no such mutations have been associated with FTLD.

Impact:

• Clarifies the central role of TDP-43 in a spectrum of neurodegenerative diseases.
• Provides a foundation for understanding the molecular pathology of ALS and FTLD.
• Highlights the potential for therapeutic strategies targeting TDP-43 dysfunction.