Leonard Petrucelli


Department of Neuroscience Mayo Clinic.

New York. EEUU

Personal Statement My  laboratory  has  been  at  the  forefront  of  research  investigating  the  cellular  mechanisms  that  cause neurodegeneration  in  diseases  characterized  by  abnormal  protein  aggregation,  such  as  Alzheimer’s  disease (AD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). Expanding upon our commitment  to  understand  the  mechanisms  of  disease  progression  and  neuronal  death,  we  now  emphasize translational research to identify biomarkers and develop therapies for treatment and prevention. We combine expertise  in  cell  and  molecular  biology,  animal  and  patient  cell  modeling,  and  drug  discovery,  to  design  and optimize selective and potent compounds that can be developed into a therapy for patients suffering from tau-, TDP-43-, and C9ORF72-related disorders. For nearly a decade, I have been investigating the mechanisms of tau degradation and exploiting this newfound knowledge to identify therapeutic strategies aimed at eliminating abnormal  tau  accumulation  associated  with  AD  and  other  tauopathies.  For  instance,  my  group  recently uncovered  histone  deacetylase  6  (HDAC6)  as  a  modulator  of  tau  aggregation  and  clearance,  and  provided evidence  that  its  manipulation  could  block  the  formation  of  pathogenic  tau  species  (Human  Molecular Genetics). As part of a collaborative effort, we published findings on the specificity and clinical utility of the tau PET  tracer  AV-1451,  which  provides  critical  insight  into  the  potential  application  as  well  as  caveats  to  the utilization of this tracer to image patients with different tauopathies (Acta Neuropathologica Communications).  We also developed an adeno-associated virus (AAV)-based mouse model of tauopathy that we anticipate will facilitate  the  identification  of  genetic  modifiers  of  disease  and  accelerate  preclinical  assessment  of  potential therapeutic approaches (Human Molecular Genetics). In fact, as Center Director of a U54 grant award, we are using  AAV-based  mouse  models  to  test  whether  genetic  diversity  influences  disease  severity  and  to  identify key genes that modulate the severity of tauopathy. Such research is possible thanks to the strong clinical and neuropathologic resources at Mayo Clinic Jacksonville, including a brain bank for neurodegenerative disorders with more than 5000 samples, which will also provide postmortem tissue from tauopathy patients in the current application. Given the complementary expertise of Drs. Fitzpatrick, Steen and myself, we are uniquely qualified to characterize the structural features and post-translational modifications that define tau and TDP-43 filaments in disease, and develop novel tools to model and detect these key aspects of pathology.