Biometal dyshomeostasis and toxic metal accumulation are common features in many neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease and Huntington’s disease. The neurotoxic effects of metal imbalance are generally associated with reduced enzymatic activities, elevated protein aggregation and oxidative stress in the central nervous system, in which a cascade of events lead to cell death and neurodegeneration. Although the links between biometal imbalance and neurodegenerative disorders remain elusive, a major class of endogenous proteins involved in metal transport has been receiving increasing attention over recent decades. The abnormal expression of these proteins has been linked to biometal imbalance and to the pathogenesis of AD. Here, we present a brief overview of the physiological roles of biometals including iron, zinc, copper, manganese, magnesium and calcium, and provide a detailed description of their transporters and their synergistic involvement in the development of AD. In addition, we also review the published data relating to neurotoxic metals in AD, including aluminum, lead, cadmium and mercury.

The gut-derived orexigenic peptide hormone ghrelin enhances neuronal firing in the substantia nigra pars compacta, where dopaminergic neurons modulate the function of the nigrostriatal system for motor coordination. Here we describe a novel mechanism by which ghrelin enhances firing of nigral dopaminergic neurons by inhibiting voltage-gated potassium Kv7/KCNQ/M-channels through its receptor GHS-R1a and activation of the PLC-PKC pathway. Brain slice recordings of substantia nigra pars compacta neurons reveal that ghrelin inhibits native Kv7/KCNQ/M-currents. This effect is abolished by selective inhibitors of GHS-R1a, PLC and PKC. Transgenic suppression of native Kv7/KCNQ/M-channels in mice or channel blockade with XE991 abolishes ghrelin-induced hyperexcitability. In vivo, intracerebroventricular ghrelin administration causes increased dopamine release and turnover in the striatum. Microinjection of ghrelin or XE991 into substantia nigra pars compacta results in contralateral dystonic posturing, and attenuation of catalepsy elicited by systemic administration of the D2 receptor antagonist haloperidol. Our findings indicate that the ghrelin/KCNQ signalling is likely a common pathway utilized by the nervous system.

Proteasome is the principal hydrolytic machinery responsible for the great majority of protein degradation. The past three decades have testified prominent advances about proteasome involved in almost every aspect of biological processes. Nonetheless, inappropriate increase or decrease in proteasome function is regarded as a causative factor in several diseases. Proteasome abundance and proper assembly need to be precisely controlled. Indeed, various neurodegenerative diseases including Parkinson’s disease (PD) share a common pathological feature, intracellular protein accumulation such as α-synuclein. Proteasome activation may effectively remove aggregates and prevent the neurodegeneration in PD, which provides a potential application for disease-modifying treatment. In this review, we build on the valuable discoveries related to different types of proteolysis by distinct forms of proteasome, and how its regulatory and catalytic particles promote protein elimination. Additionally, we summarize the emerging ideas on the proteasome homeostasis regulation by targeting transcriptional, translational, and post-translational levels. Given the imbalanced proteostasis in PD, the strategies for intensifying proteasomal degradation are advocated as a promising approach for PD clinical intervention.