ABSTRACT
Developing weaver mutant (wv/wv) mice expressing point mutation (G156S) in Gprotein-coupled inward rectifying potassium (GIRK) channel were used to explore the basic molecular mechanism of progressive neurodegeneration in Parkinson’s disease. No overt clinical abnormality was observed within 7 days of postnatal life. Hypersensitivity to light, sound, touch, and electrical stimulation concomitant with jumping behavior was noticed within 14 days. Parkinsonism, characterized by stiff neck, drooping body posture, tremors, difficulty in walking, and ataxic body movements, was noticed within 28 days. Progressive neurodegenerative changes were observed primarily in the striatum, hippocampus, and cerebellar cortex. Striatal DA, 3H-DA uptake, Zn+2, and coenzyme Q10 were reduced, whereas homovalinic acid to DA ratios, Fe3+, Ca2+, lipid peroxidation, and α-syn indices were increased. MPTP or rotenone-induced DA release was reduced; whereas salsolinol and HVA release were increased. Various hallmarks of apoptosis including caspase-3, TNF-α, NF-κ-β, metallothionein (MT-1, 2), and complex-1 nitration were increased; whereas glutathione, complex-1, ATP, and Ser (40)-phosphorylation of tyrosine hydroxylase were reduced as compared to control wild-type (controlwt), αsynuclein knock out (α-synko), metallothionein knock out (MTdko), and metallothioneintransgenic (MTtrans) mice. Although MTdko mice were susceptible to MPTP-Parkinsonism, they did not exhibit progressive nigrostriatal neurodegeneration as observed in wv/wv mice. MTtrans and α-synko mice were resistant to MPTP-Parkinsonism. Striatal neurons of wv/wv mice exhibited age-dependent increase in densecored intraneuronal inclusions, cellular aggregation, proto-oncogenes (c-fos, c-jun, caspase-3, and GAPDH) induction,
internucleosomal DNA fragmentation, and progressive neuro-apoptosis. These data are interpreted to suggest that oxidative and nitrative stress may impair DA transporter, enhance α-syn indices, and proto-oncogene expression. Furthermore, mitochondrial dysfunction due to enhanced iron accumulation, lipid peroxidation, reduced complex-1 activity, and ATP synthesis may result in reduced Ser-40-phosphorylation of TH, and hence DA synthesis and cellular apoptosis. These early molecular events may trigger progressive neurodegeneration and hence Parkinsonism, which was ameliorated by coenzyme Q10 treatment in wv/wv mice.
