Although the neuronal ceroid lipofuscinoses (NCLs) are primarily considered as neurodegenerative, glia have increasingly been implicated in NCL pathogenesis. Activated astrocytes and microglia are prominent in NCL brains, with localized glial activation preceding neuron loss in the most vulnerable CNS regions. Evidence from primary cultures of CLN1 glia suggest that microglia are dysfunctional and cross prime astrocytes to kill neurons, further supporting the need to investigate how microglia may be compromised in this disorder. To gain mechanistic insights into microglial dysfunction in CLN1 disease and how these cells may respond to treatment, we performed single-cell RNA sequencing of microglia from 3-month-old wild type (WT) and Ppt1-/- mice, with and without enzyme replacement therapy (ERT). Because CD68 positive microglia appear in the spinal cord before the brain, microglia were isolated from both regions allowing us to explore if they are affected differently. Clustering analysis identified microglial subpopulations with distinct transcriptomic profiles featuring increased expression of disease associated microglial (DAM) markers in Ppt1-/- vs. WT samples, including genes prominent in other neurodegenerative diseases such as Apoe, and other lysosomal genes such as Ctsd. This increased expression of DAM markers was mitigated by ERT especially in the brain, where the transcriptomic profile more closely resembles WT samples. In contrast, the ERT treated Ppt1-/- spinal cord showed more similarity to untreated Ppt1-/- samples, suggesting that intracerebroventricular delivery of ERT may not effectively reach spinal microglia. This may explain why brain-targeted ERT has had relatively limited success in CLN1 disease compared to the success of ERT in CLN2 disease, highlighting the need for region-specific understanding of disease mechanisms. Our analyses are ongoing, but our findings so far underscore the importance of spatial considerations in therapeutic delivery and provide insight into microglial heterogeneity that may influence treatment outcomes in CLN1 disease.