COHEN, TODD JONATHAN
UNIV OF NORTH CAROLINA CHAPEL HILL
TDP-43 acetylation as a pathogenic modification in ALS & related proteinopathies
Motor neurone diseases|Alzheimer's disease & other dementias
protein TDP-43, DNA-Binding Proteins, Amyotrophic Lateral Sclerosis, Acetylation, Frontotemporal Lobar Degenerations
7 Project Summary/Abstract Amyotrophic Lateral Sclerosis (ALS) is a devastating motor neuron disease with a 35 year survival rate and no disease modifying therapies. TAR DNA binding protein of 43kD (TDP43) 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 TDP43 pathology, or FTLDTDP), placing ALS and FTLDTDP within a spectrum of diseases known as TDP43 proteinopathies. Although TDP43 pathology has been implicated in disease onset and progression, little is known about how TDP43 becomes aggregated leading to progressive neurodegeneration.My long term goal is to uncover the pathogenic mechanisms that promote TDP43 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.?
Project narrative Amyotrophic Lateral Sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP) represent two major TDP43 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 TDP43 proteinopathies.