A Breakthrough for Neurodegenerative Diseases

May 2015

Researchers have linked defects in a molecular motor that performs several critical functions within cells to neurodegenerative diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS) and others. But due to the motor's large size, myriad subunits and high flexibility, structural studies have previously been restricted to looking at small pieces of the whole.

Assistant Professor Gabriel C. Lander (back) with the study's first author, Research Associate, Saikat Chowdhury.

Now, biologist Gabriel C. Lander and his laboratory at The Scripps Research Institute (TSRI), in collaboration with Trina A. Schroer and her group at Johns Hopkins University, have determined the basic structural organization of the motor, called the “dynein-dynactin complex.” The breakthrough could lead to new therapies for a range of neurodegenerative disorders.

“This work gives us critical insights into the regulation of the dynein motor and establishes a structural framework for understanding why defects in this system have been linked to diseases such as Huntington's, Parkinson's and Alzheimer's,” said Dr. Lander.

The proteins dynein and dynactin normally work together on microtubules for cellular activities, such as cell division and intracellular transport of critical cargo like mitochondria and mRNA. The complex also plays a key role in neuronal development and repair. Problems with the dynein-dynactin motor system have been found in brain diseases, including Alzheimer's, Parkinson's, Huntington's and ALS. In addition, some viruses (including herpes, rabies and HIV) appear to hijack the dynein-dynactin transport system to get deep inside cells.

“Understanding how dynein and dynactin interact and work, and how they actually look, is definitely going to have medical relevance,” said Research Associate Saikat Chowdhury, a member of the Lander lab who was first author of the study.

To study the dynein-dynactin complex, Dr. Schroer's laboratory first produced individual dynein and dynactin proteins. The proteins themselves are complicated, with multiple subunits, but have been so highly conserved by evolution that they are found in almost identical form in diverse organisms, from yeast to mammals.

Drs. Chowdhury and Lander then used electron microscopy (EM) and cutting-edge image processing techniques to develop two-dimensional “snapshots” of dynein's and dynactin's basic structures. These structural data contained unprecedented detail and revealed subunits never observed before.

Drs. Chowdhury and Lander next developed a novel strategy to purify and image dynein and dynactin in complex together on a microtubule – a railway-like structure, ubiquitous in cells, along which dynein-dynactin moves its cargoes.

“This is the first snapshot of how the whole dynein-dynactin complex looks and how it is oriented on the microtubule,” Dr. Chowdhury said.

The structural data clarify how dynein and dynactin fit together on a microtubule, how they recruit cargoes and how they manage to move those cargoes consistently in a single direction.

Drs. Lander and Chowdhury now hope to build on the findings by producing a higher-resolution, three-dimensional image of the dynein-dynactin-microtubule complex, using an EM-related technique called electron tomography.

“The EM facility at TSRI is the best place in the world to push the limits of imaging complicated molecular machines like these,” said Dr. Lander.

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