Causal relationship between PD-linked genes and multifactorial dopaminergic neurotoxicity. Pathogenic mutations in multiple PD genes disrupt basic cellular functions in dopaminergic neurons. Aggregation of α-synuclein is increased under conditions of oxidative or nitrosative stress that activate c-Abl, leading to accumulation of phosphotyrosine 39 (P-Y39) in brain tissues and Lewy bodies. Activation of c-Abl also impairs catalytic activity of parkin, inhibiting its proteosomal and mitochondrial functions. Abnormal associations of α-synuclein with the mitochondria cause mitochondrial membrane permeabilization and dysfunction. Aggregated α-synuclein impairs various basic cellular functions along the nigrostriatal pathway, culminating in dopaminergic neurotoxicity. A pathogenic link between defective protein sorting and PD is exemplified by pathogenic mutations in α-synuclein, LRRK2, VPS35, and DNAJC6 [DnaJ Heat Shock Protein Family (Hsp40) Member C6]. Mutations in α-synuclein, LRRK2, GBA, or ATP13A2 also impair the lysosomal-autophagy pathway and interfere with lysosomal degradation of several substrates, most notable of which is α-synuclein, setting forth feed-forward cycles of lysosomal toxicity and LB pathology. This figure was drawn by I-Hsun Wu. Copyright JHU/ICE. Permission granted by JHU/ICE.

PINK1 and parkin at the foci of mitochondrial quality control. PINK1 and parkin are central to the regulation of multiple sequential and parallel pathways that promote mitochondrial removal and regeneration. Activation of PINK1 and parkin in response to widespread mitochondrial damage leads to clearance of damaged organelles via mitophagy. Turnover of damaged mitochondrial components is facilitated by PINK/parkin-mediated generation of mitochondria-derived vesicles (MDV) that are transported to lysosomes for degradation. To replenish functional mitochondria, PINK1 and parkin target the pathogenic substrate PARIS for sequential phosphorylation and proteosomal degradation, relieving PARIS repression of PGC-1α to stimulate mitochondrial biogenesis. Besides PINK1, antioxidant properties of DJ-1 protect against oxidative stress. IRS, insulin response sequence; Mfn, Mitofusin; NRF1, Nuclear Respiratory Factor 1; Ub, ubiquitin; VDAC, voltage-dependent anion channel. This figure was drawn by I-Hsun Wu. Copyright JHU/ICE. Permission granted by JHU/ICE.

Potential interventions to curb α-synuclein spreading. Multiple routes are known to facilitate cell-to-cell spread of α-synuclein fibrils, including direct diffusion, endocytosis, or specific receptor-mediated uptake. Endocytosed fibrils are trafficked to lysosomes, and acidic environments in lysosomes favor aggregate formation, essentially serving as nucleation sites. Eventual rupture of these lysosomes plant α-synuclein aggregates in the cytosol forming intracellular pathologic inclusions that continue to grow by recruiting and sequestering other soluble cytosolic proteins. Blocking fibril transmission and enhancing lysosomal substrate degradation could curb interneuronal propagation and thus hold therapeutic potential. Targeting α-synuclein receptors such as LAG3 or APLP1 using specific antibodies could be neuroprotective. Eliminating pathogenic interactions between α-synuclein and microglia in the extracellular milieu could dampen neurotoxic inflammatory responses in the brain. If progressed stages of the disease are associated with increased exosomal release, pathogenic α-synuclein containing exosomes in body fluids could be accessed for quantification as a potential biomarker of disease progression. Strategies aimed at promoting enhanced clearance of extracellular α-synuclein using immunotherapy could be beneficial. This figure was drawn by I-Hsun Wu. Copyright JHU/ICE. Permission granted by JHU/ICE.

PAR-mediated dopaminergic cell death pathways. Hyperactivation of PARP1 and cellular accumulation of PAR lead to neuronal cell death via parthanatos. PARP1 can be activated by the accumulation of the parkin substrate AIMP2 under conditions of parkin inactivation and pathologic α-syn (α-syn PFF)–induced oxidative and/or nitrosative stress. This leads to translocation of excess PAR to the cytosol, which promotes the mitochondrial release of AIF and its interaction with MIF. Nuclear translocation of MIF causes genomic stress, which in turn may further activate PARP1 and the ensuing parthanatos-mediated cell death. In a feed-forward loop, PAR interacts with α-syn, increasing its aggregation potential and interneuronal transmission, resulting in further cellular toxicity. This figure was drawn by Noelle Burgess. Copyright JHU/ICE. Permission granted by JHU/ICE.

Neuroinflammatory mechanisms underlying dopaminergic toxicity. Toxic forms of α-synuclein released from nigrostriatal dopamine and other susceptible neurons activate microglia that can be detrimental to dopaminergic neurons through various pathways. 1) Activated microglia can phagocytose and degrade neurons. 2) Cytokine release from activated microglia promotes microglial clustering around dopamine neurons, triggering self-perpetuating cycles of chronic neuroinflammation and eventually resulting in cell death. 3) Activation of the NLRP3 inflammasome by α-synuclein, mitochondrial damage, and ROS also leads to neurotoxic inflammatory responses. 4) Activated microglia can also elicit CD8⁺ cytotoxic T-cell response by inducing dopaminergic expression of MHC-I molecules that aid in antigen presentation. 5) Inflammatory activation of microglia can subsequently activate astrocytes and their upregulation of NF-κB responsive proinflammatory genes that lead to NO and ROS production. 6) Activated microglia also induce a subtype of reactive neurotoxic astrocytes, termed A1 astrocytes, by secreting IL-1α, TNF-α, and C1q. Transfer of α-synuclein from diseased neurons to surrounding astrocytes can also lead to induction of proinflammatory gene expression. Signaling pathways within reactive microglia and astrocytes thus hold therapeutic potential. These include blocking the formation of activated A1 astrocytes via microglia formation of IL-1 α, TNF- α, and C1q. Targeting the orphan nuclear receptor Nurr1 (NR4A2) to promote anti-inflammatory effects in microglia and astrocytes may be beneficial. Blockage of IL-1β, soluble TNF, and other cytokines or iNOS production that stem from microglial activation also holds promise as therapy. Regulation of NLRP3 inflammasome activity could counter neuroinflammatory responses. TCR, T-cell receptor. This figure was drawn by I-Hsun Wu. Copyright JHU/ICE. Permission granted by JHU/ICE.