The role of the Fe/S cluster protein CISD1 in Parkinson’s disease

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Parkinson’s disease (PD) is a neurological disorder caused by degeneration of dopaminergic neurons in a midbrain structure called the substantia nigra pars compacta. It is characterized by mitochondrial dysfunction, oxidative stress, altered iron metabolism and defective mitochondrial quality control; pathophysiological alterations which connect PD with dysfunction of CDGSH Iron Sulfur Domain 1 (CISD1), a dimeric 2Fe-2S (Fe/S) cluster-containing protein anchored in the outer mitochondrial membrane facing the cytosol. CISD1 is capable of transferring its Fe/S cluster to other proteins in response to oxidative stimuli, is important in the regulation of mitochondrial bioenergetics and morphology, and is involved in mitochondrial quality control where it is a target of PTEN-induced neuronal kinase 1 (PINK1) and ubiquitylated by the E3 ubiquitin ligase Parkin, a pathway essential in PD pathophysiology. Importantly, CISD1 knockout in mice results in a motor phenotype that resembles PD. Own preliminary data also imply a role for CISD1 in the pathophysiology of PD; we observed that neuronal knockdown of fly CISD1 increases lifespan of PINK1 knockout flies and of flies exposed to rotenone, a pharmacological PD model. We also found CISD1 to be upregulated in human midbrain dopaminergic neurons lacking PINK1. Based on these observations, we hypothesize that CISD1 transfers its Fe/S cluster to other proteins when it is ubiquitylated and degraded in response to PINK1/Parkin activation. This serves to preserve the Fe/S cluster and acts as a survival signal. In the absence of PINK1 (and probably also Parkin), CISD1 accumulates at the outer mitochondrial membrane and does not transfer its Fe/S cluster elsewhere which disturbs cellular homeostasis. In the absence of CISD1, the Fe/S cluster cannot be transferred to other proteins which also disturbs cellular homeostasis and the correct execution of mitochondrial quality control. We posit that dysfunction of this pathway debilitates dopaminergic neurons. To prove or disprove this hypothesis, we will generate Drosophila melanogaster lines and human dopaminergic neurons that lack CISD1 or express mutant alleles that affect the stability of the Fe/S cluster and use these tools to illuminate how CISD1 and the presence, absence or stability of its Fe/S cluster affects mitochondrial shape, function and quality control. We will perturb CISD1 expression in fly models of PD and study its expression in samples obtained from patients suffering from PD. We will finally identify proteins that physically and genetically interact with CISD1 in response to mitochondrial dysfunction and serve as potential acceptors for the iron-sulfur cluster. This work is of utmost interest as it comprehensively assesses multiple facets of this interesting protein in vitro and in vivo and will shed light on its role in the pathophysiology of a devastating human disease.