The research described in this dissertation offers insights into various forms of neuronal gene regulation, especially in dopamine (DA) neurons. During the progression of Parkinson’s Disease, DA neurons are among the most vulnerable neurons to degenerate. Mitochondria are widely appreciated to be involved in DA neurodegeneration. Moreover, transcripts encoding mitochondrial respiratory chain components are down-regulated in (early) PD neurons. Whereas mitochondrial genes are down-regulated in PD, we showed that down-regulation of the gene-regulator Dot1l has the opposite effect in DA neurons, increasing mitochondrial respiratory chain genes broadly. In addition, we have found genes involved in anti-oxidation, mitophagy, and ribosomes consistently up-regulated. Since Dot1l regulates the activity of genes via methylation at the histone subunit H3, lysine 79 (H3K79me), we have also studied the levels of H3K79me2 in mouse DA neurons and postmortem brains of aged and diseased individuals. Firstly, we found signs of a fast turnover of H3K79me in mouse DA neurons. Secondly, we have found that high levels of H3K79me associate with lipofuscin in the old brain. Lipofuscin consists of slow / undegradable protein aggregates that accumulate during aging. Thirdly, levels of H3K79me2 were also up-regulated in DA neurons from Parkinson’s Disease patients, though, more restricted. Our research suggests that more research on the role of Dot1l in regulating neuronal mitochondria could be very rewarding as it may further reveal the roles of Dot1l in neuronal regulation of mitochondira, aging and PD, and perhaps as a future therapeutic target.