Physiological roles of disease-associated proteins in neurodegenerative diseases.

摘要

Tat Activating Regulatory DNA Binding Protein (Tardbp or TDP-43), a highly conserved metazoan DNA/RNA binding protein thought to be involved in RNA transcription and splicing, has been linked to the pathophysiology of amyotrophic lateral sclerosis and frontotemporal lobar degeneration and is essential for early embryonic development. However, neither the physiological role of TDP-43 in the adult nor its downstream targets are well defined. To address these questions, we developed conditional Tardbp knockout mice and embryonic stem (ES) cell models. Here, we show that post-natal deletion of Tardbp in mice caused dramatic loss of body fat followed by rapid death. Moreover, conditional Tardbp knockout ES cells failed to proliferate. Importantly, high throughput DNA sequencing analysis on the transcriptome of ES cells lacking Tardbp revealed a set of downstream targets of TDP-43. We show that Tbc1d1, a gene known to mediate leanness and linked to obesity, is down-regulated in the absence of TDP-43. Finally, results from our TDP-43 associated RNA co-immunoprecipitation studies suggest that TDP-43 may regulate its target transcripts through a direct or indirect binding mechanism. In addition to aberrant metabolism, the Gemini of coiled bodies (GEMs), the nuclear structures involved in the processing of RNA, is absent in spinal motor neurons of the Tardbp knockout mice. Collectively, we demonstrate that loss of TDP-43 alters fat metabolism in the periphery and RNA processing machinery in the nervous system, likely through regulating the levels of its target mRNAs.