TDP-43 acetylation as a pathogenic modification in ALS & related proteinopathies

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

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Abstract

7.¿¿Project¿Summary/Abstract¿¿ ¿ Amyotrophic¿ Lateral¿ Sclerosis¿ (ALS)¿ is¿ a¿ devastating¿ motor¿ neuron¿ disease¿ with¿ a¿ 3¿5¿ year¿ survival¿ rate¿ and¿ no¿ disease¿modifying¿ therapies.¿ TAR¿ DNA¿binding¿ protein¿ of¿ 43kD¿ (TDP¿43)¿ is¿ a¿ nuclear¿ RNA¿ and¿ DNA¿ binding¿ protein¿ that¿ becomes¿ abnormally¿ aggregated¿ in¿ the¿ brain¿ and¿ spinal¿ cord¿of¿most¿ALS¿patients¿as¿well¿as¿a¿subset¿of¿dementia¿patients¿(frontotemporal¿lobar¿degeneration¿ with¿ TDP¿43¿ pathology,¿ or¿ FTLD¿TDP),¿ placing¿ ALS¿ and¿ FTLD¿TDP¿ within¿ a¿ spectrum¿ of¿ diseases¿ known¿as¿TDP¿43¿proteinopathies.¿¿Although¿TDP¿43¿pathology¿has¿been¿implicated¿in¿disease¿onset¿ and¿ progression,¿ little¿ is¿ known¿ about¿ how¿ TDP¿43¿ becomes¿ aggregated¿ leading¿ to¿ progressive¿ neurodegeneration.¿¿My¿long¿term¿goal¿is¿to¿uncover¿the¿pathogenic¿mechanisms¿that¿promote¿TDP¿43¿ aggregation,¿which¿will¿provide¿insights¿for¿future¿therapies¿against¿these¿debilitating¿diseases.¿¿ Post¿translational¿ modifications¿ have¿ been¿ implicated¿ in¿ the¿ progression¿ of¿ neurodegenerative¿ diseases.¿¿Using¿my¿background¿in¿acetylation¿biology,¿I¿previously¿demonstrated¿that¿acetylation¿of¿the¿ tau¿ protein¿ promotes¿ tangle¿ formation¿ in¿ Alzheimer s¿ disease¿ and¿ related¿ tauopathies¿ (Nat¿ Commun.¿ 2011~2:252).¿¿I¿have¿now¿demonstrated¿that¿TDP¿43¿is¿subject¿to¿acetylation,¿thus¿highlighting¿a¿new¿ TDP¿43¿ modification¿ that¿ is¿ potentially¿ linked¿ to¿ ALS¿ and¿ related¿ proteinopathies.¿ ¿ The¿ central¿ hypothesis¿ of¿ this¿ proposal¿ is¿ to¿ determine¿ whether¿ acetylation¿ of¿ TDP¿43¿ promotes¿ aggregation¿ and¿ neurodegeneration.¿ To¿ accomplish¿ this¿ goal,¿ I¿ will¿ acquire¿ expertise¿ in¿ neuropathology¿ from¿ the¿ mentoring¿ laboratory¿ and¿ analyze¿ TDP¿43¿ acetylation¿ in¿ ALS¿ and¿ FTLD¿TDP¿ post¿mortem¿ brain¿ and¿ spinal¿ cord¿ as¿ well¿ as¿ TDP¿43¿ transgenic¿ mice¿ characterized¿ by¿ TDP¿43¿ pathology¿ and¿ neurodegeneration.¿ To¿ directly¿ determine¿ whether¿ acetylated¿ TDP¿43¿ promotes¿ disease,¿ primary¿ neuronal¿cultures¿and¿transgenic¿mice¿expressing¿acetylated¿TDP¿43¿will¿be¿evaluated¿for¿pathological¿ hallmarks,¿ toxicity,¿ and¿ neurodegeneration¿ that¿ recapitulate¿ human¿ TDP¿43¿ proteinopathies.¿ Having¿ established¿the¿disease¿relevance¿of¿TDP¿43¿acetylation,¿the¿independent¿phase¿will¿utilize¿in¿vitro¿and¿ cell¿based¿approaches¿to¿investigate¿the¿biological¿significance¿of¿acetylation¿in¿causing¿impaired¿TDP¿ 43¿binding¿to¿target¿genes¿and¿RNAs,¿leading¿to¿a¿TDP¿43¿loss¿of¿function.¿¿Finally,¿as¿an¿independent¿ investigator,¿I¿will¿utilize¿K99¿phase¿training¿in¿neurodegenerative¿disease¿to¿generate¿a¿mouse¿model¿ of¿ hyper¿acetylated¿ TDP¿43¿ and¿ determine¿ the¿ ALS¿ phenotype¿ in¿ both¿ brain¿ and¿ skeletal¿ muscle.¿¿ These¿ innovative¿ studies¿ will¿ highlight¿ TDP¿43¿ acetylation¿ as¿ a¿ critical¿ modification¿ linked¿ to¿ the¿ progression¿of¿ALS¿and¿related¿TDP¿43¿proteinopathies.¿