Nigrostriatal α-synucleinopathy induced by viral vector-mediated overexpression of human α-synuclein: A new primate model of Parkinson's disease

Abstract

We used a high-titer recombinant adeno-associated virus (rAAV) vector to express WT or mutant human ␣-synuclein in the substantia nigra of adult marmosets. The ␣-synuclein protein was expressed in 90 -95% of all nigral dopamine neurons and distributed by anterograde transport throughout their axonal and dendritic projections. The transduced neurons developed severe neuronal pathology, including ␣-synuclein-positive cytoplasmic inclusions and granular deposits; swollen, dystrophic, and fragmented neuritis; and shrunken and pyknotic, densely ␣-synuclein-positive perikarya. By 16 wk posttransduction, 30 -60% of the tyrosine hydroxylase-positive neurons were lost, and the tyrosine hydroxylase-positive innervation of the caudate nucleus and putamen was reduced to a similar extent. The rAAV-␣-synuclein-treated monkeys developed a type of motor impairment, i.e., head position bias, compatible with this magnitude of nigrostriatal damage. and 2 for a current review). In adult monkeys, MPTP administration induces profound loss of dopamine neurons in the substantia nigra (SN) and motor impairments similar to those seen in idiopathic PD. The MPTP model, however, has two obvious limitations. First, MPTP-induced toxicity is a rapid, single-hit event, resulting in an acute onset of neurodegeneration and neurological symptoms. Second, the MPTP-affected dopamine neurons do not develop the progressive ␣-synucleinopathy (Lewy bodies and Lewy neuritis, in particular) that is the characteristic hallmark of idiopathic PD. There is thus an obvious need for a new primate model of PD where the pathogenetic mechanisms associated with ␣-synuclein (␣-syn) toxicity and nigrostriatal degeneration can be studied in species close to man.Previous studies have shown that the ␣-syn protein is a major component of the intraneuronal protein aggregates (Lewy bodies and Lewy neuritis) that are pathological hallmarks of the disease (3, 4). Moreover, point mutations in the ␣-syn gene have been shown to cause familiar PD (5, 6), suggesting that abnormal processing and͞or function of ␣-syn may trigger the neurodegenerative process. Although ␣-syn is expressed in neurons throughout the nervous system, neurodegeneration in PD is remarkably selective and is most prominent in the dopaminergic neurons of the SN. Recent studies suggest that this selective vulnerability may be due to interaction of ␣-syn with intracellular dopamine, oxidative stress, and dopamine-dependent free radical damage (7-10). This interaction probably explains why dopaminergic neurons are affected by ␣-syn at expression levels that are nontoxic to other types of cells (10-13).These in vitro data raise the possibility of generating transgenic models of PD by overexpression of the ␣-syn protein in the nigrostriatal dopamine neurons. This approach has given promising results in Drosophila (14). Nevertheless, the attempts made so far in mice, by using standard transgenic technology, have been disappointing. In the transgenic mouse strains generated to date, WT or mutated human ␣-syn have b...

Herpes simplex virus RNAi and neprilysin gene transfer vectors reduce accumulation of Alzheimer's disease-related amyloid-β peptide in vivo

“…A similar approach has been reported in animal models of Parkinson's disease, using HSV vector-mediated Alzheimer's gene therapy C-S Hong et al LV 35 or AAV, 36 to overexpress a-synuclein, and Huntington's disease, using AAV-mediated expression of expanded polyglutamine tracts 37 or LV-mediated expression of Huntingtin. 38 Aside from its intrinsic flexibility and convenience, 39 the major attraction of this type of model system is that the vector can be delivered to species that are not amenable to transgenic manipulation, such as rats and monkeys, but which have special relevance to the study of human brain function and pathology.…”

Lewy bodies

“…The mice exhibited injury to the nigrostriatal DA system and motor deficits. Adenoviral vector-selective overexpression of WT and A53T ␣-SYN in the SN in nonhuman primates caused ␣-SYN inclusions and degeneration of DA neurons (103). Overexpression of WT and mutant ␣-SYN in Drosophila resulted in intraneuronal ␣-SYN inclusions, loss of DA neurons, and motor deficits (104).…”

Domain a’ of protein disulfide isomerase plays key role in inhibiting α-synuclein fibril formation

“…Some cases of early familial PD were identified as being linked to three αSyn mutations, namely A53T, A30P, and E46K (Kruger et al 1998;Munoz et al 1997;Zarranz et al 2004), these mutations accelerate the fibrillation or oligomerization of the mutated proteins in vitro (Conway et al 2000). Overexpression of αSyn in flies (Feany and Bender 2000), mice (Masliah et al 2000), and primates (Kirik et al 2003) is sufficient to trigger PD, suggesting the important roles αSyn fibrillation plays in the disease pathogenesis.…”