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, 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 Parkinson’s disease associated neuropathology.
Mutations in the ?-synuclein (? syn) and Leucine-rich repeat kinase (LRRK2) genes have been linked with inherited and sporadic forms of Parkinson’s disease and previous research has shown that accumulation of cytotoxic ? -syn protein inside of neurons represents a key step in the pathogenesis of Parkinson’s disease. “Although earlier studies have suggested interplay between ? -syn and LRRK2, a synergistic interaction in the pathogenesis of Parkinson’s disease has not been established,” explains senior study author Dr. Huaibin.
In order to systematically investigate whether LRRK2 and ? -syn act synergistically to potentiate Parkinson’s disease, the researchers generated and characterized several types of transgenic mice that over expressed different combinations of a Parkinson’s disease related ? -syn mutation along with various forms of normal and Parkinson’s disease associated LRRK2. The researchers found that although over expression of LRRK2 alone did not cause neurodegeneration, excess LRRK2 significantly accelerated the progression of neuropathological abnormalities in transgenic mice expressing Parkinson’s disease related ? -syn.
Over expression 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 ? -syn, thereby significantly delaying the progression of Parkinson’s disease pathology in the Parkinson’s disease ? -syn transgenic mice. These findings suggest that LRRK2 exacerbates the abnormal intracellular accumulation of ? -syn.
“We have uncovered a novel function for LRRK2 in regulating the intracellular trafficking and accumulation of ? -syn in neurons and our results suggest that excessive amounts of LRRK2 or its mutants may result in abnormal neuron-damaging accumulation of ? -syn protein,” concludes Dr. Cai. “It is possible that inhibition of LRRK2 expression may provide an applicable therapeutic strategy to ameliorate ? -syn-induced neurodegeneration in Parkinson’s disease or other related neurodegenerative diseases.”
References:
1. Huaibin Cai, et al. Leucine-Rich Repeat Kinase 2 Regulates the Progression of Neuropathology Induced by Parkinson’s-Disease-Related Mutant ?-synuclein. Neuron, Volume 64, Issue 6, 807-827, 24 December 2009.
