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Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by prominent degeneration of dopaminergic neurons in the substantia nigra and aggregation of the protein α-synuclein within intraneuronal inclusions known as Lewy bodies. Ninety percent of PD cases are idiopathic while the remaining 10% are associated with gene mutations that affect cellular functions ranging from kinase activity to mitochondrial quality control, hinting at a multifactorial disease process. Mutations in  LRRK2  and  SNCA  (the gene coding for α-synuclein) cause monogenic forms of autosomal dominant PD, and polymorphisms in either gene are also associated with increased risk of idiopathic PD. Although Lewy bodies are a defining neuropathological feature of PD, an appreciable subset of patients with  LRRK2  mutations present with a clinical phenotype indistinguishable from idiopathic PD but lack Lewy pathology at autopsy, suggesting that  LRRK2 -mediated PD may occur independently of α-synuclein aggregation. Here, we examine whether LRRK2 and α-synuclein, as mediators of neurodegeneration in PD, exist in common or distinct pathways. Specifically, we review evidence from preclinical models and human neuropathological studies examining interactions between the two proteins. Elucidating the degree of interplay between LRRK2 and α-synuclein will be necessary for treatment stratification once effective targeted disease-modifying therapies are developed.

LRRK2 and α-Synuclein: Distinct or Synergistic Players in Parkinson’s Disease?