The loss of dopaminergic neurons of the nigrostriatal system underlies the onset of the typical motor symptoms of Parkinson’s disease (PD). Lewy bodies (LB) and Lewy neurites (LN), proteinaceous inclusions mainly composed of insoluble α-synuclein (α-syn) fibrils are key neuropathological hallmarks of the brain of affected patients. Compelling evidence supports that in the early prodromal phases of PD, synaptic terminal and axonal alterations initiate and drive a retrograde degeneration process culminating with the loss of nigral dopaminergic neurons. This notwithstanding, the molecular triggers remain to be fully elucidated. Although it has been shown that α-syn fibrillary aggregation can induce early synaptic and axonal impairment and cause nigrostriatal degeneration, we still ignore how and why α-syn fibrillation begins. Nuclear factor-κB (NF-κB) transcription factors, key regulators of inflammation and apoptosis, are involved in the brain programming of systemic aging as well as in the pathogenesis of several neurodegenerative diseases. The NF-κB family of factors consists of five different subunits (c-Rel, p65/RelA, p50, RelB, and p52), which combine to form transcriptionally active dimers. Different findings point out a role of RelA in PD. Interestingly, the nuclear content of RelA is abnormally increased in nigral dopamine (DA) neurons and glial cells of PD patients. Inhibition of RelA exert neuroprotection against (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) MPTP and 1-methyl-4-phenylpyridinium (MPP+) toxicity, suggesting that this factor decreases neuronal resilience. Conversely, the c-Rel subunit can exert neuroprotective actions. We recently described that mice deficient for c-Rel develop a PD-like motor and non-motor phenotype characterized by progressive brain α-syn accumulation and early synaptic changes preceding the frank loss of nigrostriatal neurons. This evidence supports that dysregulations in this transcription factors may be involved in the onset of PD. This review highlights observations supporting a possible interplay between NF-κB dysregulation and α-syn pathology in PD, with the aim to disclose novel potential mechanisms involved in the pathogenesis of this disorder.

Although long-term exposure to nicotine is highly addictive, one beneficial consequence of chronic tobacco use is a reduced risk for Parkinson’s disease. Of interest, these effects both reflect structural and functional plasticity of brain circuits controlling reward and motor behavior and, specifically, recruitment of nicotinic acetylcholine receptors (nAChR) in mesencephalic dopaminergic neurons. Because the underlying cellular mechanisms are poorly understood, we addressed this issue with use of primary cultures of mouse mesencephalic dopaminergic neurons. Exposure to nicotine (1–10 μM) for 72 hours in vitro increased dendritic arborization and soma size in primary cultures. These effects were blocked by mecamylamine and dihydro-β-erythroidine, but not methyllycaconitine. The involvement of α4β2 nAChR was supported by the lack of nicotine-induced structural remodeling in neurons from α4 null mutant mice (KO). Challenge with nicotine triggered phosphorylation of the extracellular signal-regulated kinase (ERK) and the thymoma viral proto-oncogene (Akt), followed by activation of the mammalian target of rapamycin complex 1 (mTORC1)-dependent p70 ribosomal S6 protein kinase. Upstream pathway blockade using the phosphatidylinositol 3-kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one hydrochloride] resulted in suppression of nicotine-induced phosphorylations and structural plasticity. These effects were dependent on functional DA D3 receptor (D3R), because nicotine was inactive both in cultures from D3R KO mice and after pharmacologic blockade with D3R antagonist trans-N-4-2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethylcyclohexyl-4-quinolinecarboxamide (SB-277011-A) (50 nM). Finally, exposure to nicotine in utero (5 mg/kg/day for 5 days) resulted in increased soma area of DAergic neurons of newborn mice, effects not observed in D3 receptor null mutant mice mice. These findings indicate that nicotine-induced structural plasticity at mesencephalic dopaminergic neurons involves α4β2 nAChRs together with dopamine D3R-mediated recruitment of ERK/Akt-mTORC1 signaling.

Alpha-synuclein, the major component of Lewy bodies, is thought to play a central role in the onset of synaptic dysfunctions in Parkinson's disease (PD). In particular, α-synuclein may affect dopaminergic neuron function as it interacts with a key protein modulating dopamine (DA) content at the synapse: the DA transporter (DAT). Indeed, recent evidence from our “in vitro” studies showed that α-synuclein aggregation decreases the expression and membrane trafficking of the DAT as the DAT is retained into α-synuclein-immunopositive inclusions. This notwithstanding, “in vivo” studies on PD animal models investigating whether DAT distribution is altered by the pathological overexpression and aggregation of α-synuclein are missing. By using the proximity ligation assay, a technique which allows the “in situ” visualization of protein-protein interactions, we studied the occurrence of alterations in the distribution of DAT/α-synuclein complexes in the SYN120 transgenic mouse model, showing insoluble α-synuclein aggregates into dopaminergic neurons of the nigrostriatal system, reduced striatal DA levels and an altered distribution of synaptic proteins in the striatum. We found that DAT/α-synuclein complexes were markedly redistributed in the striatum and substantia nigra of SYN120 mice. These alterations were accompanied by a significant increase of DAT striatal levels in transgenic animals when compared to wild type littermates. Our data indicate that, in the early pathogenesis of PD, α-synuclein acts as a fine modulator of the dopaminergic synapse by regulating the subcellular distribution of key proteins such as the DAT.

Parkinson’s disease (PD) is a movement disorder characterized by dopaminergic nigrostriatal neuron degeneration and the formation of Lewy bodies (LB), pathological inclusions containing fibrils that are mainly composed of α-synuclein. Dopaminergic neurons, for their intrinsic characteristics, have a high energy demand that relies on the efficiency of the mitochondria respiratory chain. Dysregulations of mitochondria, deriving from alterations of complex I protein or oxidative DNA damage, change the trafficking, size and morphology of these organelles. Of note, these mitochondrial bioenergetics defects have been related to PD. A series of experimental evidence supports that α-synuclein physiological action is relevant for mitochondrial homeostasis, while its pathological aggregation can negatively impinge on mitochondrial function. It thus appears that imbalances in the equilibrium between the reciprocal modulatory action of mitochondria and α-synuclein can contribute to PD onset by inducing neuronal impairment. This review will try to highlight the role of physiological and pathological α-synuclein in the modulation of mitochondrial functions.