α-Synuclein is a presynaptic neuronal protein that is linked genetically and neuropathologically to Parkinson's disease (PD). α-Synuclein may contribute to PD pathogenesis in a number of ways, but it is generally thought that its aberrant soluble oligomeric conformations, termed protofibrils, are the toxic species that mediate disruption of cellular homeostasis and neuronal death, through effects on various intracellular targets, including synaptic function. Furthermore, secreted α-synuclein may exert deleterious effects on neighboring cells, including seeding of aggregation, thus possibly contributing to disease propagation. Although the extent to which α-synuclein is involved in all cases of PD is not clear, targeting the toxic functions conferred by this protein when it is dysregulated may lead to novel therapeutic strategies not only in PD, but also in other neurodegenerative conditions, termed synucleinopathies.

/pdf/a-synuclein-in-parkinson-s-disease-jswzbre492.pdf

α-Synuclein in Parkinson’s Disease

a-Synuclein is a presynaptic neuronal protein that is linked genetically and neuropathologically to Parkinson’s disease (PD). a-Synuclein may contribute to PD pathogenesis in a number of ways, but it is generally thought that its aberrant soluble oligomeric conformations, termed protofibrils, are the toxic species that mediate disruption of cellular homeostasis and neuronal death, through effects on various intracellular targets, including synaptic function. Furthermore, secreted a-synuclein may exert deleterious effects on neighboring cells, including seeding of aggregation, thus possibly contributing to disease propagation. Although the extent to whicha-synuclein is involved in all cases of PD is not clear, targeting the toxic functions conferred by this protein when it is dysregulated may lead to novel therapeutic strategies not only in PD, but also in other neurodegenerative conditions, termed synucleinopathies.

a-Synuclein in Parkinson's Disease

Innate immunity was previously thought to be a nonspecific immunological programme that was engaged by peripheral organs to maintain homeostasis after stress and injury. Emerging evidence indicates that this highly organized response also takes place in the central nervous system. Through the recognition of neuronal fingerprints, the long-term induction of the innate immune response and its transition to an adaptive form might be central to the pathophysiology and aetiology of neurodegenerative disorders. Paradoxically, this response also protects neurons by favouring remyelination and trophic support afforded by glial cells.

Innate immunity: the missing link in neuroprotection and neurodegeneration?

Microglial activation and adaptive immunity have been implicated in the neurodegenerative processes in Parkinson disease It has been proposed that these responses may be triggered by modified forms of alpha-synuclein (alpha-SYN), particularly nitrated species, which are released as a consequence of dopaminergic neurodegeneration To examine the relationship between alpha-SYN, microglial activation, and adaptive immunity, we used a mouse model of Parkinson disease in which human alpha-SYN is overexpressed by a recombinant adeno-associated virus vector, serotype 2 (AAV2-SYN); this overexpression leads to slow degeneration of dopaminergic neurons Microglial activation and components of the adaptive immune response were assessed using immunohistochemistry; quantitative polymerase chain reaction was used to examine cytokine expression Four weeks after injection, there was a marked increase in CD68-positive microglia and greater infiltration of B and T lymphocytes in the substantia nigra pars compacta of the AAV2-SYN group than in controls At 12 weeks, CD68 staining declined, but B- and T-cell infiltration persisted Expression of proinflammatory cytokines was enhanced, whereas markers of alternative activation (ie arginase I and interleukins 4 and 13) were not altered Increased immunoreactivity for mouse immunoglobulin was detected at all time points in the AAV2-SYN animals These data show that overexpression of alpha-SYN alone, in the absence of overt neurodegeneration, is sufficient to trigger neuroinflammation with both microglial activation and stimulation of adaptive immunity

/pdf/targeted-overexpression-of-human-alpha-synuclein-triggers-2mxuc1b42z.pdf

Targeted Overexpression of Human Alpha-Synuclein Triggers Microglial Activation and an Adaptive Immune Response in a Mouse Model of Parkinson Disease

Parkinson's disease: Autoimmunity and neuroinflammation

To support a potential role for immune mechanisms in the destruction of substantia nigra (SN) neurons, guinea pigs were immunized with bovine mesencephalon containing SN neurons. After immunization no clinical signs of basal ganglia dysfunction appeared. However, pathological examination revealed evidence of neuronal damage in the SN in 8 of 17 guinea pigs immunized with bovine mesencephalon. No nigral pathology was noted in animals immunized with spinal cord gray matter or Freund's adjuvant alone. Accompanying the SN damage in mesencephalon-immunized guinea pigs was a 25% decrease in tyrosine hydroxylase activity in the SN and a 27% decrease in dopamine content in the striatum. Deposits of IgG were detected by immunohistochemical techniques in sections of SN from mesencephalon-immunized guinea pigs and in sections of human SN after exposure to serum from mesencephalon-immunized guinea pigs. These data document the antigenicity of SN and suggest the possibility that immune mechanisms can contribute to basal ganglia pathology.

Nigral damage and dopaminergic hypofunction in mesencephalon-immunized guinea pigs

Background Increased levels of free radicals and oxidative stress may contribute to the pathogenesis of substantia nigra (SN) injury in Parkinson disease (PD), but the initiating etiologic factors remain undefined in most cases. Objective To determine the potential importance of immune mechanisms in triggering or amplifying neuronal injury, we assayed serum samples from patients with PD to determine the ability of IgG to initiate relatively specific SN injury in vivo. Methods IgG purified from the serum of 5 patients with PD and 10 disease control (DC) patients was injected into the right side of the SN in adult rats. Coronal sections were cut from the whole brain at the level of the stereotaxic injections, stained for tyrosine hydroxylase and with cresyl violet, and cellular profiles were counted in identical brain regions at the injection and contralateral sides. The ratio of cell profile counts of the corresponding injected and uninjected regions was used as an internal standard. Results Four weeks following injection of IgG, a 50% decrease in tyrosine hydroxylase–positive cellular profiles was noted on the injected sides compared with the contralateral sides of the same animals. Similarly, applied DC IgG caused only an 18% decrease. Cresyl violet staining revealed a 35% decrease in neuronal profiles of PD IgG injected into the SN pars compacta compared with the contralateral uninjected side, whereas DC IgG caused a minimal 10% decrease. Even at 4 weeks after the PD IgG injections, perivascular inflammation and significant microglial infiltration were present near injured SN pars compacta neurons. No cytotoxic effects of PD IgG were noted in choline acetyltransferase–positive neurons after stereotaxic injections into the medial septal region. Absorption of PD IgG with mesencephalic membranes and protein A agarose gel beads removed cytotoxicity, while absorption with liver membranes did not change the cytotoxicity. Conclusions Our data suggest that PD IgG can initiate a relatively specific inflammatory destruction of SN pars compacta neurons in vivo and demonstrate the potential relevance of immune mechanisms in PD.

https://jamanetwork.com/journals/jamaneurology/articlepdf/774167/noc7536.pdf

Experimental Destruction of Substantia Nigra Initiated by Parkinson Disease Immunoglobulins

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Nigral damage and dopaminergic hypofunction in mesencephalon-immunized guinea pigs

Experimental Destruction of Substantia Nigra Initiated by Parkinson Disease Immunoglobulins