IBI Colloquium: LINE1 replication is associated with cell death and motor dysfunction in a mouse model of TDP43 neurodegeneration

Assistant Professor Dr. Roger Sher, Stony Brook University, Department of Neurobiology and Behavior, New York, USA

Abstract:

TDP43 is a nucleic acid-binding protein with essential functions such as translational regulation, stress granule formation, and retrotransposon repression. Pathological aggregates of TDP43 are seen in patients with ALS, FTD, and AD. Retrotransposable elements (RTE) are mobile elements capable of inserting copies into different genomic locations. Studies in flies have established the causal role of RTEs in mediating both the intracellular toxic effects of TDP43 and the intercellular spread of that toxicity from glia to neurons.

The role of TDP43 in RTE regulation has also been replicated in postmortem human tissue. Here, we establish the first rodent model to examine the effects of TDP43 pathology on RTEs. hTDP43-Q331K animals show hindlimb clasping and lower latency to fall on the rotarod starting at 3 months, while the hTDP43-WT animal shows a delayed onset of motor deficits beginning at 17 months. We see significant upregulation of RTEs at 1.5 and 3 months in the hTDP43-Q331K animals and at 15 months in the hTDP43-WT animals, coinciding with the onset of motor defects in each line. We used the L1-EGFP reporter mouse that expresses EGFP after a retrotransposition event occurs.

The hTDP43-Q331K and hTDP43-WT animals show significantly higher GFP-positive glia and neurons, which occur in large clusters at 3 and 6 months in the motor cortex. Interestingly, both the RTE transcript levels in the MC and the clusters of GFP-positive cells within each brain region appear transiently, becoming undetectable later. The hTDP43-Q331K animals showed a single large unilateral cluster spanning the anteroposterior axis at 6 months and anterior clusters at 3 months.

In contrast, the hTDP43-WT animals showed multiple small bilateral clusters at both times, mainly concentrated in the anterior portion of the MC. Neurons with LINE1 replication are highly likely to undergo programmed cell death, regardless of TDP43 pathology. Moreover, in the presence of TDP43 overexpression, cells close to the LINE1 replication clusters are more likely to undergo PCD than at a distance.  In conclusion, our findings suggest that TDP43-associated LINE1 replication may be associated with neuronal death and potentially facilitate a non-cell autonomous spread of toxicity in a mouse model of neurodegeneration.