Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting about 6.3 million people worldwide. PD is characterized by the progressive degeneration of dopaminergic neurons in the Substantia nigra pars compacta, resulting into severe motor symptoms. The cellular mechanisms underlying dopaminergic cell death in PD are still not fully understood, but mitochondrial dysfunction, oxidative stress and inflammation are strongly implicated in the pathogenesis of both familial and sporadic PD cases. Aberrant post-translational modifications, namely glycation and glycosylation, together with age-dependent insufficient endogenous scavengers and quality control systems, lead to cellular overload of dysfunctional proteins. Such injuries accumulate with time and may lead to mitochondrial dysfunction and exacerbated inflammatory responses, culminating in neuronal cell death. Here, we will discuss how PD-linked protein mutations, aging, impaired quality control mechanisms and sugar metabolism lead to up-regulated abnormal post-translational modifications in proteins. Abnormal glycation and glycosylation seem to be more common than previously thought in PD and may underlie mitochondria-induced oxidative stress and inflammation in a feed-forward mechanism. Moreover, the stress-induced post-translational modifications that directly affect parkin and/or its substrates, deeply impairing its ability to regulate mitochondrial dynamics or to suppress inflammation will also be discussed. Together, these represent still unexplored deleterious mechanisms implicated in neurodegeneration in PD, which may be used for a more in-depth knowledge of the pathogenic mechanisms, or as biomarkers of the disease.

Oxidative stress is a key pathological feature of Parkinson's disease (PD). GlutathioneS‐transferase pi (GSTP) is a neuroprotective antioxidant enzyme regulated at the transcriptional level by the antioxidant master regulator nuclear factor‐erythroid 2‐related factor 2 (Nrf2). Here, we show for the first time that upon MPTP‐induced oxidative stress, GSTP potentiatesS‐glutathionylation of Kelch‐like ECH‐associated protein 1 (Keap1), an endogenous repressor of Nrf2,in vivo.S‐glutathionylation of Keap1 leads to Nrf2 activation and subsequently increases expression of GSTP. This positive feedback regulatory loop represents a novel mechanism by which GSTP elicits antioxidant protection in the brain.