LRRK2-Dependent Neurodegeneration in Parkinson’s Disease

Dear Colleagues,

Parkinson’s disease is the second most common neurodegenerative disorder, affecting more than 10 million people worldwide. Parkinson’s disease has a complex etiology, with genetic factors playing a significant role not only in familiar, monogenic forms but also in idiopathic condition. Mutations in LRRK2 have been recognized as the most common genetic cause of familial Parkinson’s disease, and LRRK2 itself is considered a risk factor in idiopathic Parkinson’s disease. LRRK2 is a large multidomain protein with a GTPase and kinase catalytic core surrounded by protein–protein interaction domains. LRRK2 regulates several cellular functions, including vesicle trafficking, cytoskeletal dynamics, neurotransmitter release, synaptic plasticity, mitochondrial function, autophagy, and immune response. All of these functions are dysregulated in Parkinson’s disease, suggesting LRRK2 may play a direct or indirect role. Indeed, preclinical studies have revealed that pathogenic LRRK2 mutations, notably the p.G2019S substitution at the kinase domain, favor the degeneration of nigrostriatal dopaminergic neurons and formation of alpha-synuclein inclusions, which are neuropathological hallmarks of the disease. The enhancement of kinase activity proved to be instrumental for LRRK2-mediated neurodegeneration, leading to the development of LRRK2 kinase inhibitors as possible disease-modifying agents in Parkinson’s disease. In recognition of the intense and ever-growing research in the field, as well as the clinical relevance of this topic, this Topical Collection welcomes original papers and up-to-date reviews dealing with the mechanisms underlying the contribution of LRRK2 to the neurodegeneration associated with Parkinson’s disease.

Dr. Michele Morari
Collection Editor

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