Amyotrophic Lateral Sclerosis (ALS) is a devastating motor neuron disease with a 35 year survival rate and no diseasemodifying therapies. TAR DNAbinding protein of 43kD (TDP43) is a nuclear RNA and DNA binding protein that becomes abnormally aggregated in the brain and spinal cordofmostALSpatientsaswellasasubsetofdementiapatients(frontotemporallobardegeneration with TDP43 pathology, or FTLDTDP), placing ALS and FTLDTDP within a spectrum of diseases knownasTDP43proteinopathies.AlthoughTDP43pathologyhasbeenimplicatedindiseaseonset and progression, little is known about how TDP43 becomes aggregated leading to progressive neurodegeneration.MylongtermgoalistouncoverthepathogenicmechanismsthatpromoteTDP43 aggregation,whichwillprovideinsightsforfuturetherapiesagainstthesedebilitatingdiseases. Posttranslational modifications have been implicated in the progression of neurodegenerative diseases.Usingmybackgroundinacetylationbiology,Ipreviouslydemonstratedthatacetylationofthe tau protein promotes tangle formation in Alzheimer s disease and related tauopathies (Nat Commun. 2011~2:252).IhavenowdemonstratedthatTDP43issubjecttoacetylation,thushighlightinganew TDP43 modification that is potentially linked to ALS and related proteinopathies. The central hypothesis of this proposal is to determine whether acetylation of TDP43 promotes aggregation and neurodegeneration. To accomplish this goal, I will acquire expertise in neuropathology from the mentoring laboratory and analyze TDP43 acetylation in ALS and FTLDTDP postmortem brain and spinal cord as well as TDP43 transgenic mice characterized by TDP43 pathology and neurodegeneration. To directly determine whether acetylated TDP43 promotes disease, primary neuronalculturesandtransgenicmiceexpressingacetylatedTDP43willbeevaluatedforpathological hallmarks, toxicity, and neurodegeneration that recapitulate human TDP43 proteinopathies. Having establishedthediseaserelevanceofTDP43acetylation,theindependentphasewillutilizeinvitroand cellbasedapproachestoinvestigatethebiologicalsignificanceofacetylationincausingimpairedTDP 43bindingtotargetgenesandRNAs,leadingtoaTDP43lossoffunction.Finally,asanindependent investigator,IwillutilizeK99phasetraininginneurodegenerativediseasetogenerateamousemodel of hyperacetylated TDP43 and determine the ALS phenotype in both brain and skeletal muscle. These innovative studies will highlight TDP43 acetylation as a critical modification linked to the progressionofALSandrelatedTDP43proteinopathies.
8.??Project?narrative?? ? Amyotrophic?Lateral?Sclerosis?(ALS)?and?frontotemporal?lobar?degeneration?(FTLD?TDP)?represent?two? major?TDP?43?proteinopathies?with?no?effective?treatment?strategies.??The?proposed?studies?will?provide? insights?into?the?underlying?mechanism?of?TDP?43?aggregation?and?highlight?acetylated?TDP?43?as?a? therapeutic?target?and?potential?biomarker?for?patients?with?ALS?and?related?TDP?43?proteinopathies.?? ?
| Wang, Ping; Wander, Connor M; Yuan, Chao-Xing et al. (2017) Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program. Nat Commun 8:82 |
| Cohen, Todd J; Hwang, Andrew W; Restrepo, Clark R et al. (2015) An acetylation switch controls TDP-43 function and aggregation propensity. Nat Commun 6:5845 |
