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A recent pathological hypothesis of Parkinson’s disease suggests that at the time of disease onset, midbrain dopaminergic cells lose their synaptic connectivity before dying. The preposition that dopaminergic axons degenerate initially and predominantly in PD offers new critical opportunities for the development of neuroprotective and restorative therapies. However, we know little about how dopaminergic neurons innervate their target areas. Because of their functional importance in PD, understanding the mechanisms underlying the development and function of midbrain dopaminergic circuits is of considerable interest. Therefore, the initial focus of my research was on exploring novel pathways governing the development of dopaminergic circuitry. Using a mouse model, my work defined a novel role for Nolz1, a developmentally expressed transcription factor, in regulating aspects of dopaminergic axon growth and target innervation. I show that Nolz1 regulates critical aspects of striatal development in the mouse embryo and that aberrant striatal patterning alters the outgrowth of nigrostriatal projection neurons (Chapter 2). The premature degeneration of axonal projections in PD has been linked to changes in mitochondrial function. Impairment of mitochondrial dynamics, transport, and loss of plasticity of axon terminals precedes the onset of neuronal degeneration in this neurodegenerative disease. PINK1 is a mitochondrial kinase that ensures mitochondrial health and mutations in PINK1 cause PD. My work explored how mutations in PINK1 alter cellular metabolism, using a Drosophila model of PD. Multi-omics analysis of pink1 mutant flies uncovered metabolic and transcriptional modifications in cysteine metabolism which coincided with defects in mitochondrial respiration. These findings confirmed PINK1’s canonical role in mitochondrial function, while highlighting the relevance of cysteine metabolism to compensate for early and selective defects in mitochondrial respiration and ATP production (Chapter 3). To answer if we can recapitulate these changes in a human model, I then used human induced pluripotent stem cells (iPSCs). I differentiated human induced pluripotent stem cells (iPSCs) carrying a recently discovered I368N mutation in PINK1 into neural precursor cells (NPCs) and examined their metabolic profile. I found that the PINK1 I368N mutation causes global metabolic changes that broadly validate the comprehensive number of hits recovered in pink1 mutant flies, suggesting a significant overlap between my integrated networks. This convergence of disease phenotypes points to a common disease mechanism that may offer a unifying perspective on early-stage PD pathology (Chapter 4). Together, these results shed light on novel genes and pathways that could be exploited for therapeutic intervention.

In December 2019, a coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began infecting humans, causing a novel disease, coronavirus disease 19 (COVID-19). This was first described in the Wuhan province of the People's Republic of China. SARS-CoV-2 has spread throughout the world, causing a global pandemic. To date, thousands of cases of COVID-19 have been reported in the United Kingdom, and over 45,000 patients have died. Some progress has been achieved in managing this disease, but the biological determinants of health, in addition to age, that affect SARS-CoV-2 infectivity and mortality are under scrutiny. Recent studies show that several medical conditions, including diabetes and hypertension, increase the risk of COVID-19 and death. The increased vulnerability of elderly individuals and those with comorbidities, together with the prevalence of neurodegenerative diseases with advanced age, led us to investigate the links between neurodegeneration and COVID-19. We analysed the primary health records of 13,338 UK individuals tested for COVID-19 between March and July 2020. We show that a pre-existing diagnosis of Alzheimer's disease predicts the highest risk of COVID-19 and mortality among elderly individuals. In contrast, Parkinson's disease patients were found to have a higher risk of SARS-CoV-2 infection but not mortality from COVID-19. We conclude that there are disease-specific differences in COVID-19 susceptibility among patients affected by neurodegenerative disorders.

Peer reviewed: True, Funder: AstraZeneca; Id: http://dx.doi.org/10.13039/100004325, Funder: University of Cambridge; Id: http://dx.doi.org/10.13039/501100000735, Parkinson's disease (PD), an age-dependent neurodegenerative disease, is characterised by the selective loss of dopaminergic neurons in the substantia nigra (SN). Mitochondrial dysfunction is a hallmark of PD, and mutations in PINK1, a gene necessary for mitochondrial fitness, cause PD. Drosophila melanogaster flies with pink1 mutations exhibit mitochondrial defects and dopaminergic cell loss and are used as a PD model. To gain an integrated view of the cellular changes caused by defects in the PINK1 pathway of mitochondrial quality control, we combined metabolomics and transcriptomics analysis in pink1-mutant flies with human induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) with a PINK1 mutation. We observed alterations in cysteine metabolism in both the fly and human PD models. Mitochondrial dysfunction in the NPCs resulted in changes in several metabolites that are linked to cysteine synthesis and increased glutathione levels. We conclude that alterations in cysteine metabolism may compensate for increased oxidative stress in PD, revealing a unifying mechanism of early-stage PD pathology that may be targeted for drug development. This article has an associated First Person interview with the first author of the paper.

In December 2019, a coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began infecting humans, causing a novel disease, coronavirus disease 19 (COVID-19). This was first described in the Wuhan province of the People&rsquo, s Republic of China. SARS-CoV-2 has spread throughout the world, causing a global pandemic. To date, thousands of cases of COVID-19 have been reported in the United Kingdom, and over 45,000 patients have died. Some progress has been achieved in managing this disease, but the biological determinants of health, in addition to age, that affect SARS-CoV-2 infectivity and mortality are under scrutiny. Recent studies show that several medical conditions, including diabetes and hypertension, increase the risk of COVID-19 and death. The increased vulnerability of elderly individuals and those with comorbidities, together with the prevalence of neurodegenerative diseases with advanced age, led us to investigate the links between neurodegeneration and COVID-19. We analysed the primary health records of 13,338 UK individuals tested for COVID-19 between March and July 2020. We show that a pre-existing diagnosis of Alzheimer&rsquo, s disease predicts the highest risk of COVID-19 and mortality among elderly individuals. In contrast, Parkinson&rsquo, s disease patients were found to have a higher risk of SARS-CoV-2 infection but not mortality from COVID-19. We conclude that there are disease-specific differences in COVID-19 susceptibility among patients affected by neurodegenerative disorders.

Funder: Vetenskapsrådet (Swedish Research Council); doi: https://doi.org/10.13039/501100004359, Midbrain dopaminergic (DA) axons make long longitudinal projections towards the striatum. Despite the importance of DA striatal innervation, processes involved in establishment of DA axonal connectivity remain largely unknown. Here we demonstrate a striatal-specific requirement of transcriptional regulator Nolz1 in establishing DA circuitry formation. DA projections are misguided and fail to innervate the striatum in both constitutive and striatal-specific Nolz1 mutant embryos. The lack of striatal Nolz1 expression results in nigral to pallidal lineage conversion of striatal projection neuron subtypes. This lineage switch alters the composition of secreted factors influencing DA axonal tract formation and renders the striatum non-permissive for dopaminergic and other forebrain tracts. Furthermore, transcriptomic analysis of wild-type and Nolz1−/− mutant striatal tissue led to the identification of several secreted factors that underlie the observed guidance defects and proteins that promote DA axonal outgrowth. Together, our data demonstrate the involvement of the striatum in orchestrating dopaminergic circuitry formation.