Our major research goals are to investigate the cellular mechanisms that cause neurodegeneration in diseases characterized by abnormal protein aggregation and to develop therapeutic strategies for their treatment. Such diseases include Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis and Parkinson's disease.

Our research efforts are aimed at gaining insight regarding the processes that initiate the abnormal aggregation of certain proteins, such as tau and TDP-43, as well as the harmful consequences resulting from the formation of these aggregates. Importantly, our studies seek to uncover novel approaches and new therapeutics that can prevent or reverse the neurotoxic processes that contribute to the pathogenesis of neurodegenerative proteinopathies.

Targeting tau as a treatment for tauopathies

The accumulation of proteinaceous aggregates is a pathological hallmark of many neurological diseases characterized by neuronal dysfunction and eventual cell death. In tauopathies, these aggregates take the form of neurofibrillary tangles composed of abnormally modified tau. This group of diseases includes Alzheimer's disease, frontal temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, Pick's disease and corticobasal degeneration. Therapeutics aimed at eliminating abnormal tau are thus of considerable interest for the treatment of Alzheimer's disease and related tauopathies. However, the identity of all abnormal, and presumably toxic, tau species is not definitively known.

While the removal of as-yet-identified tau products from the brain may, at first glance, seem a daunting task, we believe it is possible to enhance the clearance of harmful tau products by harnessing the abilities of heat shock proteins. This group of proteins, which regulates protein quality control, has evolved to recognize and remove abnormally folded proteins, such as hyperphosphorylated tau from affected cells.

TDP-43: A new player in neurodegenerative disease

Like tau, TDP-43 is a protein known to abnormally aggregate and is associated with a number of neurodegenerative diseases. TDP-43 is a principal component of ubiquitin-positive inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U).

With regards to inherited forms of FTLD-U, TDP-43 inclusions are observed in cases linked to chromosome 9p and in patients with mutations in the genes encoding valosin-containing protein and progranulin. TDP-43 pathology is also observed, to varying degrees, in other neurodegenerative disorders, including Alzheimer's disease, hippocampal sclerosis, Lewy body disease, parkinsonism-dementia complex of Guam, corticobasal degeneration, Pick's disease and Perry syndrome. Of note, TDP-43 is normally a nuclear protein but neurons with cytoplasmic inclusions have a substantial loss of nuclear TDP-43.

TDP-43 also exhibits a disease-specific biochemical signature; pathologically altered TDP-43 is hyperphosphorylated and cleaved to generate C-terminal fragments in affected brain and spinal cord regions. Currently, we are undertaking a multi-tiered approach to determine how TDP-43 truncation and phosphorylation contribute to the pathogenesis of TDP-43 proteinopathies and to investigate the involvement of abnormal progranulin and TDP-43 in neurotoxicity.

About Dr. Petrucelli

Leonard Petrucelli, Ph.D., is a professor of neuroscience at Mayo Clinic College of Medicine and Science in Florida. His research focuses on investigating presence of aberrant proteins in patients with neurodegenerative diseases.