Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration

Nat Neurosci, 2019 · DOI: 10.1038/s41593-018-0293-z · Published: February 1, 2019

Simple Explanation

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with the loss of TDP-43 from the nucleus of cells. This paper identifies that TDP-43 controls the production of stathmin-2, a factor associated with neuronal growth. When TDP-43 levels are low, its binding to stathmin-2 pre-mRNA is reduced, exposing a hidden signal that leads to the production of a shortened, non-functional mRNA. This results in reduced levels of stathmin-2. Restoring stathmin-2 expression can restore the ability of axons to regenerate. This suggests that the reduction in stathmin-2, caused by problems with TDP-43, is a key factor in why neurons become more vulnerable in ALS/FTD.

Study Duration

Not specified

Participants

Fibroblast lines from ALS patients and controls, iPSC-derived motor neurons

Evidence Level

Not specified

Key Findings

1
TDP-43 regulates the expression of stathmin-2, a neuronal growth-associated factor, by binding to sites within the first intron of stathmin-2 pre-mRNA.
2
Reduced TDP-43 levels lead to the utilization of a cryptic polyadenylation site in stathmin-2 pre-mRNA, resulting in a truncated, non-functional mRNA and decreased stathmin-2 expression.
3
Restoring stathmin-2 expression in iPSC-derived motor neurons can rescue axonal regenerative capacity, even in the absence of normal TDP-43 function.

Research Summary

This study identifies that TDP-43 regulates the expression of stathmin-2, a neuronal growth-associated factor, and that reduced TDP-43 levels lead to the utilization of a cryptic polyadenylation site in stathmin-2 pre-mRNA, resulting in a truncated, non-functional mRNA and decreased stathmin-2 expression. The researchers found reduced stathmin-2 expression in neurons from ALS patients and in iPSC-derived motor neurons depleted of TDP-43, suggesting that stathmin-2 loss of function is a key driver of motor neuron degeneration. Importantly, restoration of stathmin-2 levels rescues axonal regeneration ability in the absence of TDP-43, supporting rescue of stathmin-2 levels as a potential therapeutic approach in neurodegenerative diseases affected by TDP-43 proteinopathy.

Practical Implications

Therapeutic Target

Restoration of stathmin-2 levels could be a potential therapeutic strategy for ALS, FTD, and other neurodegenerative diseases affected by TDP-43 proteinopathy.

Diagnostic Marker

Premature polyadenylation of stathmin-2 mRNA could serve as a diagnostic marker for ALS and FTD, particularly in sporadic and C9orf72-expansion mediated cases.

Understanding ALS Pathogenesis

The findings provide a direct link between TDP-43 dysfunction and neuronal vulnerability in ALS by demonstrating that stathmin-2 loss inhibits motor axon regeneration.

Study Limitations

1
The study primarily focuses on stathmin-2 and TDP-43, while other factors may also contribute to neurodegeneration in ALS and FTD.
2
The cryptic polyadenylation signal and GU-rich sequences in intron one of the human stathmin-2 gene are not found in mice, limiting the translatability of the abnormal processing of stathmin-2 into a mouse model.
3
The study does not fully elucidate the global impact of TDP-43 on alternative polyadenylation in human motor neurons, requiring further investigation.

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