Abstract
DJ-1, a causative gene product of an autosomal recessive familial form of Parkinson’s disease (PD), plays roles in reducing oxidative stress and transcriptional regulation. Loss of its function is thought to result in the onset of PD. DJ-1 has been demonstrated to show general cytoprotective function mainly through antioxidant properties and possibly regulates the extent of stroke-induced damage and neurodegeneration in Alzheimer’s disease (AD). The paper, “Effects of a DJ-1-Binding Compound on Spatial Learning and Memory Impairment in a Mouse Model of Alzheimer’s Disease”, by Kitamura et al. in this issue of Journal of Alzheimer’s Disease reports that a DJ-1 modulator UCP0054278/compound B (comp-B), which has been previously shown to exhibit antioxidant and neuroprotective properties in PD models, can prevent neurodegenerative changes and cognitive dysfunction in an animal model of AD. Indeed, comp-B reduces not only α-synuclein but also insoluble Aβ42 levels, prevents the reductions in synaptophysin and drebrin, and rescues cognitive deficits in transgenic APdE9 mice model of AD. It is noteworthy that pharmacological modulation of a familial PD gene product is sufficient to modify biochemical phenotypes and cognitive performance in amyloid-based genetically driven mouse models of AD. Together with mixed pathology in the vast majority of the patients with late-onset dementia, these findings strongly suggest the existence of common pathogenesis of diverse neurodegenerative disorders. Anti-oxidative strategy such as DJ-1 modulation is one of the major candidates to address the common pathogenesis and should be assembled among multimodal or combinatory interventions against neurodegenerative disorders.
Mutations in DJ-1 cause an autosomal recessive, early onset familial form of Parkinson’s disease (PD), PARK7 [1]. DJ-1 plays roles in reducing oxidativestress (OS) and transcriptional regulation [2–5], and loss-of-function mutations lead to the characteristic selective neurodegeneration of nigrostriatal dopaminergic neurons. Of particular importance, the cytoprotective roles of DJ-1 are not restricted to the process of neurodegeneration in PD, but are more generally involved in diverse neuronal damage including stroke and Alzheimer’s disease (AD) [6–9]. DJ-1 expression decreases markers of OS in vivo, where DJ-1 protects through alleviation of OS with the essential role of the oxidation-sensitive cysteine-106 residue [6]. Therefore, the general neuroprotective functions of DJ-1 make it a promising target for novel therapeutic approaches to treat age-related neurodegenerative diseases [9].
In this issue of Journal of Alzheimer’s Disease, Kitamura et al. report that a DJ-1 modulator UCP0054278/compound B (comp-B), which has been previously shown to exhibit antioxidant and neuroprotective properties in PD models, can prevent neurodegenerative changes and cognitive dysfunction in an animal model of AD [10]. Comp-B reduces not only α-synuclein but also insoluble Aβ42 levels, prevents the reductions in synaptophysin and drebrin, and rescues cognitive deficits in transgenic APdE9 mice model of AD. Intriguingly, pharmacological modulation of a familial PD gene product is sufficient to modify biochemical phenotypes and cognitive performance in a genetically modified animal model of AD with amyloid-driven neurodegeneration. These observations strongly support the notion that there should be pathogenesis common to diverse neurodegenerative disorders, which is supported also by mixed pathology of Aβ, hyperphosphorylated tau, α-synuclein, and TDP-43 in the vast majority of the patients with late-onset dementia [11].
The brain is particularly vulnerable to OS because of its high rate of oxygen consumption, abundant lipid content, and relative paucity of antioxidant enzymes compared with other organs [12, 13]. A modest level of OS is essential to maintain cellular physiological function through the activation of stress resistance systems. However, when the level of OS increases beyond the compensation of antioxidant defense, cellular macromolecules are oxidatively damaged. Many lines of evidence have indicated that OS is involved not only in the process of brain aging but also in the pathogenesis of neurodegenerative disorders, including AD and PD [13, 14]. Indeed, several disease-causing gene mutations in AD (AβPP, PSEN1, PSEN2) and PD (PARKIN, PINK-1, DJ-1) as well as AD susceptibility gene polymorphism (APOE4) are associated with increases in oxidative damage and/or vulnerability to oxidative insults. Moreover, known risk factors of AD (traumatic brain injury, cerebral infarcts, diabetes mellitus, hypertension, hypercholesterolemia, and hyperhomocysteinemia) and PD (traumatic brain injury and exposure to metals, pesticides, and herbicides) are associated with increased OS [12, 14]. Of particular note, patients at the preclinical stages of AD and PD, as well as disease models using induced pluripotent stem cells (iPSCs) andgenetically modified animals, provide consistent evidence that oxidative insult is a significant early event in the pathological cascade of AD and PD [13–16]. OS and associated key pathological events commonly found in AD and PD [11] are shown in Fig. 1. Therefore, OS is a promising target particularly of preemptive strategies against AD, PD, and other chronic neurodegeneration.
It is speculated that, in the future approaches for prevention and early intervention of AD, specific anti-AD therapy (i.e., anti-Aβ and/or anti-hyperphosphorylated tau strategies) will be combined with lifestyle interventions targeting general brain health to jointly combat the disease [17, 18]. In this context, anti-oxidative strategy such as DJ-1 modulation is one of the major candidates to address the common pathogenesis and should be assembled among multimodal or combinatory interventions against neurodegenerative disorders.
DISCLOSURE STATEMENT
Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/16-0878r1).