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

Abstract

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.

The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity

“…Major contributors to the sporadic form of the disease, in addition to aging, are exposure to pesticides and other toxins such as rotenone, paraquat and MPP+ that increase ROS production and activate mPTP [ 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 ]. The familial forms of Parkinson’s disease result from mutations in a number of proteins: mitochondrial proteins that participate in mitophagy, PINK1 and Parkin [ 186 , 227 ], LRRK2, a protein that participates in fission [ 228 , 229 , 230 , 231 ], several ATG proteins that participate in autophagy [ 212 ] and α-synuclein [ 231 ]. Thus, the majority of the familial forms of the disease result from mutations in proteins that participate in different stages of mitophagy/autophagy, indicating that the disruption of mitophagy is a major cause of the familial form of the disease [ 212 ].…”

The Nigral Coup in Parkinson’s Disease by α-Synuclein and Its Associated Rebels

“…The PD-linked G2019S mutation in LRRK2 enhances α-synuclein propagation efficiency by Ras-related protein Rab-35 phosphorylation [ 104 ]. The interaction of LRRK2 and α-synuclein has been reviewed recently in detail by O´Hara et al [ 105 ] Indeed, this interaction has been challenged, as post-mortem brain analyses have not shown LB in LRRK2-induced PD [ 105 , 106 ]. Experimental studies demonstrate that the expression of familial mutant G2019S LRRK2 does not dramatically elevate α-synuclein or neurodegeneration in neurons [ 107 ].…”

The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity

“…Major contributors to the sporadic form of the disease, in addition to aging, are exposure to pesticides and other toxins such as rotenone, Paraquat and MPP+ that increase ROS production and activate mPTP (218 -225). The familial forms of Parkinson's disease result from mutations in a number of proteins: mitochondrial proteins that participate in mitophagy, PINK1 and Parkin (185,226), LRKK2, a protein that participates in fission (227 -230), several ATG proteins that participate in autophagy (211), and α-synuclein (230). Thus, the majority of the familial forms of the disease results from mutations in proteins that participate in different stages of mitophagy/autophagy, indicating that disruption of mitophagy is a major cause of the familial form of the disease (211).…”