Genetics and Pathogenesis of Parkinson's Syndrome

Abstract

Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops a virtually unique form of Parkinson's syndrome. Clinical manifestations consist of variable motor and nonmotor features, and myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central and peripheral nervous systems, the distribution varies and other pathologies commonly modify PD or trigger similar manifestations. Nearly all PD is genetically influenced. More than 100 genes or genetic loci have been identified, and most cases likely arise from interactions among many common and rare genetic variants. Despite its complex architecture, insights from experimental genetic dissection coalesce to reveal unifying biological themes, including synaptic, lysosomal, mitochondrial, andimmune-mediated mechanisms of pathogenesis. This emerging understanding of Parkinson's syndrome, coupled with advances in biomarkers and targeted therapies, presages successful precision medicine strategies.

Keywords: GBA; LRRK2; Parkinson's disease; alpha-synuclein; functional genomics; heterogeneity; lysosome; mitochondria; oligogenic; parkinsonism; synapse.

Figure 1

Neuropathologic features of Lewy body diseases (a,b,c) and other causes of parkinsonism (d). (a) Macroscopic appearance of the midbrain in (i) a patient without parkinsonism and (ii) a patient with Lewy body dementia (LBD), highlighting the superior colliculus (SC), red nucleus (RN), cerebral peduncle (CP), and substantia nigra (SN). In LBD, SN pigmentation is lost, whereas tectal (SC) and tegmental (RN) volumes are unaffected. Relative preservation of midbrain volume helps distinguish PD from mimics, such as progressive supranuclear palsy (PSP). (b) Classic Lewy body morphology in the SN on the basis of microscopic examination, including (i) a cytoplasmic inclusion with a dense eosinophilic core, concentric lamellae, and a pale-staining peripheral rim (hematoxylin and eosin stain). The Lewy body displaces neuromelanin (Nm) pigment within the cytoplasm. (ii) An immunostain for alpha-synuclein (αSyn) shows the dense staining of the peripheral rim of an inclusion, with less dense staining of the core. The tortuous, αSyn-positive structure below is a Lewy neurite. (iii) Electron microscopy of an extracellular Lewy body in the SN shows the characteristic dense core (Cr), here with sparse lipid droplets (Lp), a looser filamentous rim, and the adjacent neuropil with axons (Ax). (c) Other Lewy body morphologies, including (i) cortical Lewy bodies (white arrows) from temporal neocortex and (ii) pale bodies (Pb) from SN. (iii) An immunostain shows diffuse αSyn labeling of a Pb. (iv,v) Electron microscopy reveals noncompact, granulofilamentous material (Fil), entrapping and displacing cytoplasmic organelles (Cyt), and the adjacent neuropil with axons (Ax). The region enclosed by the white square is magnified (v), showing filamentous material that is sharply demarcated by Nm granules. (d) Pathologic heterogeneity of parkinsonism. Diffuse amyloid plaques are shown from a patient with LBD (i), along with characteristic pathology from several tauopathies with prominent parkinsonism, including (ii) tau-positive SN neuronal inclusions in chronic traumatic encephalopathy (CTE), (iii) a p62-positive tufted astrocyte from the striatum in PSP, and (iv) a tau-positive astrocytic plaque from the frontal cortex in corticobasal degeneration (CBD). (v) Multiple system atrophy (MSA) is characterized by αSyn-positive oligodendroglial cytoplasmic inclusions (black arrows); however, other pleomorphic, including intranuclear, inclusions are also commonly seen in neurons (white arrow).

Figure 2

Genetic architecture of Parkinson’s disease (PD). (a) PD risk alleles have a wide spectrum of frequencies and effect sizes (penetrance). Many PD risk alleles also show age-dependent penetrance. The manifestation of familial versus nonfamilial PD depends on allele penetrance, age, and the presence of genetic and environmental modifiers. (b) Allelic heterogeneity of synuclein-alpha (SNCA). Copy number variants (duplication) and both common (rs356168) and rare (p.A53T) single-nucleotide variants affecting SNCA are associated with PD risk. Locus duplication and common regulatory variants that enhance gene promoter activity increase overall gene expression levels. Rare variants promote SNCA protein aggregation. (c) Conceptual model for how PD genetic variants (arrows i–iv) might affect risk and overall course of disease (orange lines). The black dotted line represents the baseline population PD risk and disease trajectory. Genetic risk factors might influence (i) the earliest formation and propagation of disease pathology or (ii) the conversion from preclinical to prodromal disease (first clinical symptoms). It is also possible that genes modify (iii) the overall tempo of PD clinicopathologic progression. Beyond PD initiation and progression, genetic factors might plausibly impact (iv) the heterogeneous manifestations of PD, such as the presence and severity of specific motor and nonmotor features.

Figure 3

Parkinson’s disease (PD) genes implicate synaptic and lysosomal mechanisms. (a) The synapse. Synaptic transmission is initiated when a presynaptic nerve terminal releases neurotransmitters, via exocytosis, into the synaptic cleft, resulting in a response in the postsynaptic cell. Synaptic vesicles are recycled by clathrin-mediated endocytosis and refilled with neurotransmitters. DNAJC6, SYNJ1, GAK, and SH3GL2 participate in clathrin-coated vesicle endocytosis and recycling, whereas VPS35, LRRK2, and RAB7L1 modulate endolysosomal trafficking. Under physiological conditions, alpha-synuclein (αSyn) regulates neurotransmitter release possibly via pleiotropic actions, including endocytosis, synaptic vesicle clustering, and exocytosis. (b) The lysosome. αSyn reaches the lysosome either through endocytosis or autophagy. Membrane lipids are also trafficked within the endolysosomal system. Many PD genes encode lysosomal proteins involved in the degradation of lysosomal contents (CTSB) and membrane lipids (GBA, SMPD1, GALC), the proper trafficking of lysosomal enzymes (SCARB2), and the maintenance of the compartmental milieu (ATP13A2, TMEM175).