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Synergistic interaction enhances pathogenesis of Parkinson's disease

Date:
December 24, 2009
Source:
Cell Press
Summary:
Scientists have identified a synergistic interaction that disrupts normal intracellular transport mechanisms and leads to the accumulation of neuron-damaging clumps of protein associated with Parkinson's disease (PD), a neurodegenerative disorder that is characterized by a specific loss of neurons in the midbrain and brainstem. The research identifies a new potential therapeutic option for preventing PD-associated neuropathology.

Scientists have identified a synergistic interaction that disrupts normal intracellular transport mechanisms and leads to the accumulation of neuron-damaging clumps of protein associated with Parkinson's disease (PD), a neurodegenerative disorder that is characterized by a specific loss of neurons in the midbrain and brainstem. The research, published by Cell Press in the December 24 issue of the journal Neuron, identifies a new potential therapeutic option for preventing PD-associated neuropathology.

Mutations in the alpha--synuclein (α-syn) and Leucine-rich repeat kinase (LRRK2) genes have been linked with inherited and sporadic forms of PD and previous research has shown that accumulation of cytotoxic α-syn protein inside of neurons represents a key step in the pathogenesis of PD. "Although earlier studies have suggested interplay between α-syn and LRRK2, a synergistic interaction in the pathogenesis of PD has not been established," explains senior study author Dr. Huaibin Cai from the Laboratory of Neurogenetics at the National Institutes of Health in Bethesda, Maryland.

In order to systematically investigate whether LRRK2 and α-syn act synergistically to potentiate PD, Dr. Cai and colleagues generated and characterized several types of transgenic mice that overexpressed different combinations of a PD-related alpha-syn mutation along with various forms of normal and PD-associated LRRK2. The researchers found that although overexpression of LRRK2 alone did not cause neurodegeneration, excess LRRK2 significantly accelerated the progression of neuropathological abnormalities in transgenic mice expressing PD-related α-syn.

Overexpression of LRRK2 disrupted key structures and mechanism that play a role in transporting proteins inside of the neurons. Importantly, genetic disruption of LRRK2 maintained normal intracellular transport and reduced the accumulation of α-syn, thereby significantly delaying the progression of PD pathology in the PD α-syn transgenic mice. These findings suggest that LRRK2 exacerbates the abnormal intracellular accumulation of α-syn.

"We have uncovered a novel function for LRRK2 in regulating the intracellular trafficking and accumulation of α-syn in neurons and our results suggest that excessive amounts of LRRK2 or its mutants may result in abnormal neuron-damaging accumulation of α-syn protein," concludes Dr. Cai. "It is possible that inhibition of LRRK2 expression may provide an applicable therapeutic strategy to ameliorate α-syn-induced neurodegeneration in PD or other related neurodegenerative diseases."

The researchers include Xian Lin, National Institute on Aging, National Institutes of Health, Bethesda, MD; Loukia Parisiadou, National Institute on Aging, National Institutes of Health, Bethesda, MD; Xing-Long Gu, National Institute on Aging, National Institutes of Health, Bethesda, MD; Lizhen Wang, National Institute on Aging, National Institutes of Health, Bethesda, MD; Hoon Shim, National Institute on Aging, National Institutes of Health, Bethesda, MD; Lixin Sun, National Institute on Aging, National Institutes of Health, Bethesda, MD; Chengsong Xie, National Institute on Aging, National Institutes of Health, Bethesda, MD; Cai-Xia Long, National Institute on Aging, National Institutes of Health, Bethesda, MD; Wan-Jou Yang, National Institute on Aging, National Institutes of Health, Bethesda, MD; Jinhui Ding, National Institute on Aging, National Institutes of Health, Bethesda, MD; Zsu Zsu Chen, University of Alabama at Birmingham, Birmingham, AL; Paul E. Gallant, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Jung-Hwa Tao-Cheng, National Institutes of Health, Bethesda, MD; Gay Rudow, The Johns Hopkins University School of Medicine, Baltimore, MD; Juan C. Troncoso, The Johns Hopkins University School of Medicine, Baltimore, MD; Zhihua Liu, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; Zheng Li, National Institute of Mental Health, National Institutes of Health, Bethesda, MD; and Huaibin Cai, National Institute on Aging, National Institutes of Health, Bethesda, MD.


Story Source:

The above story is based on materials provided by Cell Press. Note: Materials may be edited for content and length.


Cite This Page:

Cell Press. "Synergistic interaction enhances pathogenesis of Parkinson's disease." ScienceDaily. ScienceDaily, 24 December 2009. <www.sciencedaily.com/releases/2009/12/091223125121.htm>.
Cell Press. (2009, December 24). Synergistic interaction enhances pathogenesis of Parkinson's disease. ScienceDaily. Retrieved July 24, 2014 from www.sciencedaily.com/releases/2009/12/091223125121.htm
Cell Press. "Synergistic interaction enhances pathogenesis of Parkinson's disease." ScienceDaily. www.sciencedaily.com/releases/2009/12/091223125121.htm (accessed July 24, 2014).

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