Abstract
Author SummaryThe major pathological event in Parkinson disease is the loss of dopaminergic neurons in a midbrain structure, the substantia nigra. The study of familial Parkinson disease has uncovered several disease-associated genes, including DJ-1. Subsequent studies have suggested that the DJ-1 protein is a suppressor of oxidative stress that might modify signaling pathways that regulate cell survival. However, because animal models lacking DJ-1 function do not show dopaminergic neurodegeneration, the function(s) of DJ-1 in vivo remain unclear. Using mouse genetics, we found that DJ-1 is required for survival of neurons of the substantia nigra only in aging conditions and only in neurons that are partially impaired in receiving trophic signals. Aging mice that lack DJ-1 and Ret, a receptor for a neuronal survival factor, lose more dopaminergic neurons in the substantia nigra as compared with aging mice that lack only Ret. Using the fruit fly Drosophila, we determined that DJ-1 interacts with constitutively active Ret and with its associated downstream signaling pathways. Therefore, understanding the molecular connections between trophic signaling, cellular stress and aging could facilitate the identification of new targets for drug development in Parkinson Disease.
Highlights
Specific and progressive loss of substantia nigra (SN) neurons is the central pathogenic event in Parkinson disease (PD), the most common movement neurodegenerative disorder, characterized by tremor, rigidity, and bradykinesia
We found that DJ-1 is required for survival of neurons of the substantia nigra only in aging conditions and only in neurons that are partially impaired in receiving trophic signals
In cultured SH-SY5Y neuroblastoma cells, endogenous Ret expression was not modified when DJ-1 expression was downregulated by RNAi, nor were the levels of endogenous DJ-1 changed when these cells were stimulated with glial cell line-derived neurotrophic factor (GDNF) (Figure S1); Ret and DJ-1 protein levels appear to be regulated by separate mechanisms
Summary
Specific and progressive loss of substantia nigra (SN) neurons is the central pathogenic event in Parkinson disease (PD), the most common movement neurodegenerative disorder, characterized by tremor, rigidity, and bradykinesia. Transgenic mouse models that reproduce the genetic defects found in familial PD showed limited power in reproducing disease pathology, and most of them fail to exhibit degeneration of SN neurons [4] (see [5]). This together with the fact that familial PD accounts for less than 10% of all PD cases (the rest being sporadic) suggests that multiple hits, including environmental factors, underlie selective neuronal death [6]
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