Leonard Petrucelli, M.D., Ph.D.

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SUMMARY

The Neurodegenerative Diseases Laboratory of Leonard Petrucelli, Ph.D., is at the forefront of research investigating the cellular mechanisms that cause diseases characterized by abnormal protein aggregation such as Alzheimer's disease, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In expanding upon his commitment to understanding the causes of such diseases, Dr. Petrucelli is now emphasizing translational research geared toward identifying and developing therapies for treatment and prevention.

Focus areas

• Mechanisms of disease progression and neuronal death. Dr. Petrucelli's team recently discovered a hallmark of C9orf72-linked FTD and ALS (c9FTD/ALS): c9RAN proteins (dipeptide repeats). These proteins result from a mutation in the C9orf72 gene. His team is investigating the significance of c9RAN proteins in various cell models, including patient-derived fibroblasts, and in vivo systems.
• Development of novel therapeutic agents. In working to identify small-molecule drug candidates, the lab recently discovered that inhibition of the enzyme HDAC6 may be an effective strategy to effectively arrest the toxic accumulation of tau protein, which is associated with Alzheimer's disease and related dementia. In collaboration with the lab of Matthew David Disney, Ph.D., at Scripps Florida, Dr. Petrucelli's team also discovered small molecules that target RNA defects in c9FTD/ALS.
• Biomarkers for diagnosis and treatment. By developing and characterizing novel biomarker assays, the lab seeks to develop diagnostic tools to determine whether a patient has ALS or FTD and to track disease progression or severity. Dr. Petrucelli's team has shown that detection of c9RAN proteins in cerebrospinal fluid of patients carrying the C9orf72 mutation holds promise as a potential biomarker. More recently, his group has identified a novel tau protein that can be detected in Alzheimer's disease patients.

Significance to patient care

Dr. Petrucelli's lab aims to identify molecular culprits, including identifying the role epigenetic events may play in disease, and to develop therapeutic strategies to improve the prognosis for patients with neurodegenerative disorders. By combining expertise in drug discovery, cell biology and induced pluripotent stem cell (iPSC) modeling, his lab aims to design and optimize selective and potent compounds that can be developed into a therapy for patients who have C9orf72-related disorders and develop therapeutic inhibitors for the treatment of Alzheimer's disease and FTD. Given no biomarker currently exists for clinicians to definitively diagnose ALS or FTD, identifying potential biomarkers and therapeutic targets may greatly aid future drug discovery.

Professional highlights

• Award on the Aging Nervous System; Robert and Arlene Kogod Center on Aging, Department of Neuroscience and Department of Neurology; Mayo Clinic; 2024.
• National Institutes of Health:
  • Invited member, Cellular and Molecular Biology of Neurodegeneration study section, 2011-2016.
  • Director, P01NS084974, "Pathobiology of Neurodegeneration in C9orf72 Repeat Expansion,” 2014.
• Ralph B. and Ruth K. Abrams Professor, Mayo Clinic, 2015.
• Member, Alzheimer's Disease Research Grant Advisory Board, Florida Department of Health, 2014.
• Health Care Heroes award for research, Jacksonville Business Journal, 2014.
• "Best Advances of 2013" for discovery of c9RAN proteins, Editorial Advisory Board, Neurology Today, 2013.
• Scientific Advisory Board, Alzforum, 2007-2009.