Given the wide variety of phenotypes exhibited by the different a-Syn transgenic models, mechanistic conclusions from these models can be difficult for a casual observer. However, closer examinations of the transgenic mouse models do reveal significant mechanistic insights into the in vivo pathogenesis of a-synucleinopathy.
The most important implication of various a-Syn transgenic models is that we can conclude that a-Syn abnormalities cause neuronal dysfunction and neurodegeneration in vivo. Thus, even in diseases where the cause is not genetic mutations in the a-Syn gene, such as in most sporadic PD cases, the presence of a-Syn abnormalities indicates that these abnormalities are some how mechanistically linked to neurodegeneration in human disease. Further, a-Syn pathology in human a-synucleinopathies and the transgenic mouse models share significant biochemical and structural features. Thus, the transgenic mouse models of a-synucleinopathy can provide significant insights into the in vivo evolution of a-Syn abnormalities.
The main common feature of all transgenic models of a-synucleinopathy is that aging is required for expression of neurologic phenotype, neuropathology, and the aggregation of a-Syn. This is particularly true for the transgenic mouse models. In most transgenic mouse models, once the neurologic and/or neuropathologic phenotypes are expressed, they are progressive with aging. This progressive nature of the neurodegenerative phenotype is unknown for the viral, vector-based models. Regardless, the transgenic mouse models seem recapitulate the most significant risk factor for human a-synucleinopathy. It is significant that the effects of aging are one feature that is not easily reproduced in cellular models of a-Syn toxicity. Currently, it is not known what aspect of aging is responsible for promoting a-Syn-dependent neurodegeneration. Aging may lead to changes in the cell biology of a-Syn, promoting the pathologic conversion of a-Syn (61). For example, brain maturation and aging are associated with reduced rate of a-Syn degradation and increase in the accumulation of oxidatively modified a-Syn (61). Thus, aging may facilitate the formation and accumulation of toxic aggregates and oligomers of a-Syn. This may be a significant factor in the a-Syn transgenic mice using the pan-neuronal promoters since the onset of the disease phenotype appears to be temporally connected to onset of a- Syn aggregation in these mice. However, aging is not simply associated with the onset of a-Syn aggregation, since progressive loss of DAergic neurons in TH(9.0)-hm2aSyn transgenic mice occurs without signs of a-Syn aggregation in DAergic neurons. Thus, it is also likely that older neurons are more sensitive to any toxicity associated with a-Syn abnormalities.
Not surprisingly, the levels of transgene expression is a major factor in modeling a-synucleinopathy in these models. Despite the differences in clinical and pathologic features of various a-Syn transgenic models, neurologic abnormalities and neuropathology are clearly more severe with the higher levels of transgene expression. This aspect, together with the genetic data showing the pathogenic importance of gene dosage and promoter activity in human PD (9), is consistent with the view that a-Syn causes disease via dominant gain of deleterious property. The fact a-Syn knockout mice do not exhibit progressive neurodegenerative phenotype also supports this conclusion.
Another unique feature of the a-Syn transgenic mouse models is that differential pathogenic potentials of wild type and mutant human a-Syn can be demonstrated. In studies where transgenic mice expressing comparable levels of different Hua-Syn variants were generated by the same group, it is clear that the expression of mutant a-Syn can cause abnormalities more readily than the wild type a-Syn (18,19,39). Further, in one study where the A30P and A53T mutant a-Syn encoding transgenes were expressed at comparable levels in transgenic mice, it was clear that A53T mutant was more pathogenic than the A30P mutant (19). Since all Hua-Syn variants appear equally toxic in the invertebrate transgenic models and virally transduced models of a-synucleinopathy (17,23,24), apparent differences in the pathogenic potential of the Hua-Syn variants are one of the unique features of transgenic mouse models.
In all mammals, including humans, a-Syn is widely expressed in multiple neuronal populations. However, the fact that only a certain neuronal subset is more consistently affected by a-synucleinopthy in humans suggests that certain neuronal populations are more vulnerable to develop a-Syn abnormalities. Similarly, differential vulnerability of different neuronal populations in developing a-synucleinopathy is modeled by the a-Syn transgenic mouse models, where a-Syn expression is driven by the pan-neuronal promoters such as Thy1 and PrP (18,19). Both mouse Thy1 and PrP promoters drive very high levels of expression in most neuronal populations, particularly in cortex and hippocampus. However, the cortical regions are relatively spared from neuropathology in these mice. Thus, it is clear that relative resistance of human forebrain regions from developing a-synucleinopathy can be recapitulated in trans-genic mice. Significantly, in transgenic mice where Hua-Syn transgene is expressed throughout the nervous system, the mice develop a-synucleinopathy in the overlapping populations of neurons (e.g., red nucleus, colliculi, deep cerebellar nuclei, pontine reticular nuclei, and spinal motor neurons). The fact that similar populations of neurons are affected in the lines of mice generated by multiple independent groups using two different promoters indicates that, in rodents, these neuronal populations are particularly vulnerable to developing a-synucleinopathy in mice. Even in viral vector-based models, where Hua-Syn causes neurodegeneration without significant a-Syn aggregation, there is a clear cell-type specificity in terms of toxicity. Specifically DAergic neurons in ventral tegmental area (62) and non-DAergic neurons in SN (24) are resistant to Hua-Syn induced neurodegeneration. Thus, defining the basis for this increased vulnerability may provide significant insights into the pathogenesis of a-synucleinopathy.
Another level of neural cell-type differences regarding the development of a-synucleinopathy is indicated by transgenic mouse models of MSA. As previously noted, a-Syn-dependent abnormality occurs in CNP-a-Syn transgenic mice with the modest levels of wild type a-Syn expression. Given that much higher levels of wild type Hua-Syn expression with the pan-neuronal promoter do not cause neuropathology in transgenic mice, an obvious implication is that oligodendrocytes are extremely vulnerable to developing a-synucleinopathy. Given the potential enhanced sensitivity of oligodendrocytes to a-synucleinopathy, defining the source of the oligodendrocyte a-Syn in human MSA is clearly warranted.
Despite the potential increased vulnerability of certain neuronal populations in developing a-synucleinopathy, the primary differences among the various promoters used may explain apparent variations in the distribution of neuropathology associated with various a-Syn transgenic mice. The effects of the promoter on the resulting neuropathology are obviously demonstrated by the transgenic mouse lines where a-Syn expression is limited to oligodendrocytes or TH-positive neurons. However, promoter-dependent effects may also effect pathology and phenotypes in transgenic mice generated with "pan-neuronal" promoters. For example, the difference in the pathology of Thy1aSyn/PrP-aSyn and PDGF-aSyn transgenic mice may be due to the fact that the human a-Syn expression in the PDGF-aSyn transgenic mice is more restricted than in the pThy-1-haSyn transgenic mice (63). In particular, low transgene expression in subcortical regions with the PDGF-promoter is likely basis for the lack of brain stem pathology in the PDGF-aSyn transgenic mice. In addition, compared to the pThyl-promoter, PDGF^-promoter drives significant amount human a-Syn expression in glial cells (63). Considering that relatively modest levels of wild type human a-Syn can cause neuropathology in the transgenic mouse models of MSA, the glial expression of ha-Syn in PDGF-haSyn mice could contribute to neuronal dysfunction in these mice.
Thus far, it has been disappointing that none of the a-Syn transgenic mouse models recapitulate both a-Syn abnormalities and robust DAergic degeneration. It is not clear why most of the Hua-Syn transgenic mouse models have significant abnormalities in DAergic neurons, particularly in light of the dramatic pathologic changes in drosophila DAergic neurons (17), DA-dependent a-Syn toxicity in human neuronal cultures (64), and DAergic degeneration with viral transduction (23,24). It is important that in transgenic mouse models where DAergic degeneration is present, neurodegeneration is present without robust a-Syn aggregation (e.g., TH9.0-hm2aSyn) and only at very advanced ages (>12 months of age) (54,55). Possibly, the aggressive onset and rapid progression of non-DAergic pathology with pan-neuronal expression of Hua-Syn may preclude development of DAergic pathology in the Thy-1 and the PrP promoter based transgenic mouse models. It should be noted that the currently used pan-neuronal promoters drive expression of a-Syn in neurons, such as motor neurons, that normally express relatively low levels of a-Syn. For example, lower endogenous levels of a-Syn expression in motor neurons may be a natural adaptation of these neurons. Thus, it is possible that the use of an alternative promoter that better reflects the endogenous pattern of a-Syn expression may provide a model with both progressive DAergic and non-DAergic phenotype.
It is also significant to note that DAergic neurodegeneration in a few trans-genic mouse lines (PDGF and pTH9.0) and virally transduced rodents are rarely associated with obvious aggregation of a-Syn in DAergic neurons. In contrast, other transgenic mouse models of a-synucleinopathy, including the models of MSA, are always associated with robust aggregation of a-Syn. This difference suggests that DAergic neurons in rodents are relatively resistant to developing a-Syn aggregates. This idea is supported by the in vitro studies showing that DA and DA metabolites can inhibit a-Syn aggregation (65). The lack of a-Syn aggregates in DAergic neurons also suggests that the insoluble a-Syn aggregates may not be the primary toxic species responsible for DAergic neurodegeneration. Collectively, the observations with various a-Syn transgenic models suggest the possibility of two distinct pathways for a-Syn-dependent neurodegeneration. Specifically, a-Syn aggregates may cause neurodegeneration of nonDAergic neurons, whereas a-Syn-dependent DAergic neurodegeneration involve soluble a-Syn oligomer and other signaling pathways. This hypothesis is consistent with the proposal that a-Syn abnormalities in DAergic neurons are a relatively late event in PD pathogenesis (2,3).
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