IU Researchers Receive Grant to Study Role of Misfolded Protein in Neurodegenerative Diseases

A $4.8 million grant will support researchers from Indiana University School of Medicine and the Medical Research Council Laboratory of Molecular Biology to study how human neurodegenerative diseases are affected by the misfolding of the protein TDP-43.

Misfolding occurs when a protein adopts a conformation which differs from the native one. The researchers, funded by the National Institute of Neurological Disorders and Stroke, have developed an innovative approach to deciphering the role of TDP-43 misfolding in the pathology of frontotemporal dementias, limbic predominant age-related TDP-43 encephalopathy and Alzheimer’s disease.

The goals of the project are to determine whether the presence of atypical neuropathologic features may signal novel neurodegenerative disorders and whether each disorder is characterized by distinct alterations to TDP-43. An important aim of this study is to determine atomic structures of misfolded TDP-43.

“The presence of misfolded proteins in the central nervous system is the hallmark of neurodegenerative diseases,” said Kathy Newell, MD, Jay C. and Lucile L. Kahn Professor of Alzheimer's Disease Research and Education at IU School of Medicine and a principal investigator of the project. “The argument for the pathogenic significance of various misfolded proteins results from the fact that mutations in the various genes encoding those proteins cause distinct genetically determined neurodegenerative diseases. Furthermore, misfolding of those proteins also occurs in sporadic neurodegenerative diseases.”

An international, multidisciplinary team has been assembled with expertise in neuropathology, digital pathology, molecular genetics, biochemistry, protein misfolding, proteomics, structural biology and cryogenic electron microscopy. The team is supported by experts in clinical neurology, protein misfolding and biostatistics, as well as by the Dementia Laboratory’s Brain Library.

“The protein TDP-43 is central to the pathogenesis of half of all frontotemporal lobar degeneration cases. Finding out how TDP-43, when misfolded, gives rise to multiple proteinopathies is extremely important for the design of diagnostic and therapeutic compounds that will target pathologic TDP-43,” Newell said.

The project is called “Investigating the role of TDP-43 mislocalization, structure, and post-translational modifications in the neuropathologically heterogeneous TDP-43 proteinopathies.”

In addition to Newell, the other principal investigators are Laura Cracco, PhD, MS, assistant research professor of pathology and laboratory medicine at IU School of Medicine and Benjamin Ryskeldi-Falcon, PhD, group leader at the Medical Research Council Laboratory of Molecular Biology in the United Kingdom. This project is the first National Institutes of Health funded research for all three investigators as principal investigators.