The molecular mechanisms underlying neurodegeneration

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We have found that CHIP and Hsp70 interact with Parkin, a protein whose genetic mutations are responsible for autosomal recessive juvenile parkinsonism(AR-JP). Parkin, Hsp70 and CHIP form a high molecular-weight complex in vivo. Hsp70 and CHIP have negative and positive regulatory function on the ubiquitin ligase activity of Parkin under in vitro conditions, respectively. Moreover, Co-overexpression of Parkin, with Hsp70 and CHIP lead to enhanced degradation of Pael-R, a Parkin substrate, suggesting that Hsp70 and CHIP coordinately regulate Parkin function. Regarding mutant superoxide dimutase 1(SOD 1)-related ALS, we crossed XIAP and p35,overexpressing transgenic(Tg) mice with mutant SOD1 Tg ALS model mice. In XIAP and mutant SOD1 double Tg mice, the disease progression was slowed compared with mutant SOD1 Tg mice. In contrast, p35 and mutant SOD1 crossed mice, the disease progression was not affected. XIP, but not p35 inhibits caspase-9. Moreover, casepase-9 was activated in the spinal motor neurons of sporadic ALS, suggesting that cappase-9 plays a key role in the disease progression of ALS. We also crossed GluR2 Tg mouse with ALS model mouse and found that the disease onset was significantly delayed in the double transgenic mouse. GluR2 overexpression renders spinal motoneuronal AMPA receptors calcium-impermeable. In double transgenic mice, oxidative stress was also attenuated and age-dependant misfolding of mutant SOD1 was markedly suppressed. These results indicate that calcium-permeable AMPA receptors aggravate the clinical course of mutant-SOD1 related ALS model mice.