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Improper Protein Digestion in Neurons Identified as a Cause of Familial Parkinson’s

Published: Friday, March 08, 2013
Last Updated: Friday, March 08, 2013
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Researchers at CUMC and others have discovered how the most common genetic mutations in familial Parkinson’s disease damage brain cells.

The mutations block an intracellular system that normally prevents a protein called alpha-synuclein from reaching toxic levels in dopamine-producing neurons. The findings suggest that interventions aimed at enhancing this digestive system, or preventing its disruption, may prove valuable in the prevention or treatment of Parkinson’s. The study was published March 3 in the online edition of the journal Nature Neuroscience.

Parkinson’s disease is characterized by the formation of Lewy bodies (which are largely composed of alpha-synuclein) in dopamine neurons. In 1997, scientists discovered that a mutation in alpha-synuclein can lead to Lewy body formation. “But alpha-synuclein mutations occur in only a tiny percentage of Parkinson’s patients,” said co-lead author David L. Sulzer, PhD, professor of neurology, pharmacology, and psychiatry at CUMC. “This meant that there must be something else that interfered with alpha-synuclein in people with Parkinson’s.”

Dr. Sulzer and his colleagues suspected that a gene called leucine-rich repeat kinase-2 (LRRK2) might be involved. LRRK2 mutations are the most common mutations to have been linked to Parkinson’s. The current study aimed to determine how these mutations might lead to the accumulation of alpha-synuclein.

“We found that abnormal forms of LRRK2 protein disrupt a critical protein-degradation process in cells called chaperone-mediated autophagy,” said Dr. Sulzer. “One of the proteins affected by this disruption is alpha-synuclein. As this protein starts to accumulate, it becomes toxic to neurons.” Delving deeper, the researchers found that LRRK2 mutations interfere with LAMP-2A, a lysosome membrane receptor that plays a key role in lysosome function.

(Chaperone-mediated autophagy, or CMA, is responsible for transporting old or damaged proteins from the cell body to the lysosomes, where they are digested into amino acids and then recycled. In 2004, Dr. Sulzer and the current paper’s other co-lead author, Ana Maria Cuervo, MD, PhD, professor of developmental & molecular biology, of anatomy & structural biology, and of medicine at Albert Einstein College of Medicine of Yeshiva University, showed that alpha-synuclein is degraded by the CMA pathway.)

“Now that we know this step that may be causing the disease in many patients, we can begin to develop drug treatments or genetic treatments that can enhance the digestion of these disease-triggering proteins, alpha-synuclein and LRRK2, or that remove alpha-synuclein,” said Dr. Sulzer.

While LRRK2 mutations are the most common genetic cause of Parkinson’s, it is too early to tell whether these findings, and therapies that might stem from them, would apply to patients with non-familial Parkinson’s, the more common form of the disease. “Right now, all we can say is that it looks as though we’ve found a fundamental pathway that causes the buildup of alpha-synuclein in people with LRRK2 mutations and links these mutations to a common cause of the disease. We suspect that this pathway may be involved in many other Parkinson’s patients,” said Dr. Sulzer.

The study involved mouse neurons in tissue culture from four different animal models, neurons from the brains of patients with Parkinson’s with LRRK2 mutations, and neurons derived from the skin cells of Parkinson’s patients via induced pluripotent stem (iPS) cell technology. All the lines of research confirmed the researchers’ discovery.

The paper is titled “Interplay of LRRK2 with chaperone-mediated autophagy.” The other contributors are Samantha J. Orenstein (Einstein), Sheng-Han Kuo (CUMC), Inmaculada Tasset (Einstein), Esperanza Arias (Einstein), Hiroshi Koga (Einstein), Irene Fernandez-Carasa (University of Barcelona, Barcelona Spain), Etty Cortes (CUMC), Lawrence S. Honig (CUMC), William Dauer (University of Michigan, Ann Arbor, MI), Antonella Consiglio (University of Barcelona and University of Brescia, Brescia, Italy), and Angel Raya (Insitucio Catalana de Recerca I Estudies Avancas and Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine, Barcelona, Spain).

The collaboration of Sulzer and Cuervo was supported by a Udall Center of Excellence for Research in Parkinson’s Disease of the NIH National Institute of Neurological Disorders and Stroke. This work was further supported by grants from the JPB Foundation, the National Institute on Aging (AG031782 and AG08702); the Rainwater Foundation; the Beatrice and Roy Backus Foundation; the Parkinson’s Disease Foundation; Fondazione Guido Berlucchi; and Centers for Networked Biomedical Research, Ministry of Economy and Competitiveness and by a Hirschl/Weill-Caulier Career Scientist Award and a gift from Robert and Renee Belfer.

The authors declare no financial or other conflicts of interest.

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