Exploring the pathological interaction between LRRK2 and alpha-synuclein

Abstract

Parkinson’s disease (PD) is the most common age-related neurodegenerative movement disorder that affects 1-2% of the general population over the age of 65 and rising to 4-5% over 80 years of age. It is estimated that 6.3 million people worldwide have Parkinson’s disease and 1.2 million in the European Union (EU) alone. As the disease progresses, patients frequently develop a mask-like facial expression, festinating gait and cognitive impairment and the final clinical symptoms are muscle rigidity, bradykinesia, resting tremor and postural instability in addition to non-motor problems that result in a marked reduction in quality of life. The motor symptoms of PD arise from the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) leading to a deficiency of the neurotransmitter dopamine (DA) in the striatum. While dopamine replacement therapy is initially effective in treating the motor symptoms of PD, there is no known cure or neuroprotective therapy for this debilitating disease. Although the pathology underlying the disease is well defined, it is still unclear why DAergic neurons degenerate and die. PD is generally considered as a sporadic disease of unknown etiology, however in the last two decades it has become clear that heritability plays an important role in the pathogenesis of PD. Of the different genes associated with familial disease, mutations in two genes encoding for α-synuclein and leucine-rich repeat kinase 2 (LRRK2) proteins cause autosomal dominant PD. One of the neuropathological hallmarks of idiopathic and some familial forms of PD are Lewy bodies, which are intracytoplasmic inclusions that are enriched with fibrillar α- synuclein protein. Notably, LRRK2 mutation carriers with PD predominantly develop Lewy body pathology suggesting that LRRK2 may lie upstream of α-synuclein aggregation. These observations and other in vivo studies have suggested a common pathogenic pathway with LRRK2 potentially regulating the aggregation and neuronal toxicity of α-synuclein. However, the relationship between LRRK2 and α-synuclein in the mammalian brain is presently unclear and requires further evaluation, especially within midbrain dopaminergic neurons that degenerate in PD. The aim of this thesis work was to delineate a potential pathogenic interplay between these two PD-related gene products in mediating neurodegeneration in vivo. Understanding how and where the functional pathways of LRRK2 and α-synuclein converge will provide important insight into the common mechanisms underlying neurodegeneration in PD.[...]