Oxidative Stress and Neurodegeneration: Interconnected Processes in PolyQ Diseases

Abstract

Neurodegenerative polyglutamine (polyQ) disorders are caused by trinucleotide repeat expansions within the coding region of disease-causing genes. PolyQ-expanded proteins undergo conformational changes leading to the formation of protein inclusions which are associated with selective neuronal degeneration. Several lines of evidence indicate that these mutant proteins are associated with oxidative stress, proteasome impairment and microglia activation. These events may correlate with the induction of inflammation in the nervous system and disease progression. Here, we review the effect of polyQ-induced oxidative stress in cellular and animal models of polyQ diseases. Furthermore, we discuss the interplay between oxidative stress, neurodegeneration and neuroinflammation using as an example the well-known neuroinflammatory disease, Multiple Sclerosis. Finally, we review some of the pharmaceutical interventions which may delay the onset and progression of polyQ disorders by targeting disease-associated mechanisms.

Keywords: microglia activation; neurodegeneration; neuroinflammation; oxidative stress; polyglutamine; proteasome impairment.

Figure 1

Effects of polyQ-expanded proteins at the cellular level. PolyQ-expanded proteins induce responses from multiple cellular components including the mitochondria and the nucleus. Accumulation of mutant proteins may lead to excessive oxidative stress, mitochondrial damage, modulation of autophagy and proteasome activity and, possibly, genomic destabilization through DNA damage.

Figure 2

The interplay between neuroinflammation and neurodegeneration. Reactive microglia and infiltration of the nervous system by the peripheral immune cells may cause inflammation. Neuroinflammation may lead to oxidative stress, axonal damage, loss of cellular communication, mitochondrial dysfunction and eventually, may contribute to neurodegeneration.

Figure 3

Effects of antioxidants and UPS, autophagy, microglia modulation in polyQ animal models. Various antioxidants were repeatedly shown to exert neuroprotective effects in mouse, Drosophila and C. elegans polyQ models. Similarly, genetic or compound-mediated enhancement of UPS components and autophagy results in attenuation of the symptom manifestation and/or improvement of the animal physiology. Finally, microglia suppression was found to be beneficial in mouse polyQ models.