Dementia with Lewy bodies (DLB) is the second most common dementia, following Alzheimer’s disease, with prevalence rising significantly in people aged 65 years and older. The core pathology in DLB is progressive pathologic accumulation of misfolded α-synuclein in Lewy bodies that especially targets midbrain dopamine (DA) neurons and leads to their degeneration. This neuronal loss in response to synucleinopathy is an important source of vulnerability not only in DLB, but is also found in Alzheimer’s disease. Given the shared features across disorders, identifying mechanisms of DA neurodegeneration in response to synucleinopathy may provide critical insights into neuron vulnerability and resilience common to age-related neurodegenerative disorders. However, we still lack basic understanding of the mechanisms underlying neuronal vulnerability and resilience. Significantly, we have established complementary approaches comparing Drosophila and mouse models of age-related neurodegenerative disease. We exploit the similarities and differences between the two species to provide novel insights into evolutionarily conserved cellular and molecular pathways that affect age-related neurodegeneration. Using these approaches, we have identified the vesicular glutamate transporter VGLUT (VGLUT2 in mammals and dVGLUT in Drosophila) as a new modulator of resilience to neurodegeneration in DA neurons. Indeed, DA neurons that upregulate VGLUT expression are more resilient including in response to pathologic accumulation of α-synuclein – a conserved response in flies and mice. To elucidate VGLUT’s roles in DA neuron vulnerability, we established an innovative suite of intersectional genetic tools to selectively distinguish and manipulate DA neurons that express VGLUT in flies and mice. With these tools and models, we can now answer key questions: 1) what are the conserved mechanisms regulating expression of DA neuron VGLUT in synucleinopathy? and 2) do regulators of VGLUT expression modulate resilience to neurodegeneration caused by synucleinopathy? To address this, we take advantage of the fly’s genetic tractability to rapidly identify new targets of vulnerability and resilience and then test these candidates in mouse models of synucleinopathy. Our central hypotheses are: i) DA neuron VGLUT expression is under tight regulatory control and the genes involved are critical for VGLUT upregulation in synucleinopathy (Aim 1). ii) Upregulation of VGLUT expression is a pro-survival coping mechanism and the genes that modulate this increased VGLUT expression in DA neurons contribute to resilience in synucleinopathy (Aim 2). Using our comparative approaches, we may identify novel interventional targets conserved across species to boost resilience in DA neurons. These new targets may ultimately be tested in other cell types as a broader intervention for prevention, mitigation and treatment of neurodegeneration in DLB, Alzheimer’s disease and Alzheimer’s disease-related dementi...