Stathmin-2: adding another piece to the puzzle of TDP-43 proteinopathies and neurodegeneration

Abstract

Cytoplasmic aggregated proteins are a common neuropathological feature of neurodegenerative diseases. Cytoplasmic mislocalization and aggregation of TAR-DNA binding protein 43 (TDP-43) is found in the majority of patients with amyotrophic lateral sclerosis (ALS) and in approximately 50% of patients dying of frontotemporal lobar degeneration (FTLD). In this issue of the JCI, Prudencio, Humphrey, Pickles, and colleagues investigated the relationship of TDP-43 pathology with the loss of stathmin-2 (STMN2), an essential protein for axonal growth and maintenance. Comparing genetic, cellular, and neuropathological data from patients with TDP-43 proteinopathies (ALS, ALS-frontotemporal dementia [ALS-FTD], and FTLD-TDP-43 [FTLD-TDP]) with data from patients with non-TDP-related neurodegenerations, they demonstrate a direct relationship between TDP-43 pathology and STMN2 reduction. Loss of the normal transcription suppressor function of TDP-43 allowed transcription of an early termination cryptic axon, resulting in truncated, nonfunctional mRNA. The authors suggest that measurement of truncated STMN2 mRNA could be a biomarker for discerning TDP proteinopathies from other pathologies.

Figure 1. The puzzle of neurodegeneration.

Multiple processes and pathways leading to neurodegeneration are identified from experimental models and human neuropathology. Some of those pathways, proteins, and genes may fit together as an organized model of disease. STMN2 is shown as a central component of a pathway that includes TDP-43 proteinopathy — i.e., TDP-43 nuclear clearing, formation of phosphorylated cytoplasmic aggregates, and reduction of its normal transcription suppressor function in STMN2 mRNA. It is unclear how other pieces fit in, and still others remain missing. These same pathways are likely common to several neurodegenerative diseases. N/C transport, nucleocytoplasmic transport.