Khundadze, M. | bioRxiv Science

bioRxiv2024

Disease-associated microglia and activation of CD8+ T cells precede neuronal cell loss in a model of hereditary spastic paraplegia

In central nervous system (CNS) diseases characterized by late-onset neurodegeneration, the interplay between innate and adaptive immune responses remains poorly understood. This knowledge gap is amplified by the prolonged nature of these diseases, complicating the delineation of brain-resident and infiltrating cells. Here, we conducted a comprehensive profiling of innate and adaptive immune cells across various CNS regions in a murine model of spastic paraplegia 15 (SPG15), a complicated form of hereditary spastic paraplegia (HSP). Using fate-mapping of bone marrow-derived cells via genetic labeling, we identified microgliosis and microglial MHC-II upregulation accompanied by infiltration and local expansion of T cells in the CNS of Spg15-/- mice. Single-cell analysis revealed an increase of disease-associated microglia (DAM) and clonal expansion of effector CD8+ T cells across CNS regions occurring prior to neuronal loss. Analysis of potential cell-cell communication pathways suggested bidirectional interactions between DAM and effector CD8+ T cells potentially contributing to disease progression in Spg15-/- mice. In summary, we identified a shift in microglial phenotypes associated with recruitment and clonal expansion of T cells as a new characteristic of Spg15-driven neuropathology. Targeting activated microglia, CD8+ T cells and their communication represent promising avenues to prevent the loss of neuronal function in HSP.

immunology↗

bioRxiv2024

Renal proximal tubules are sensitive to metabolic acidosis

Patients suffering from distal renal tubular acidosis (dRTA) are sometimes diagnosed with proximal tubule dysfunction with leaks of phosphate, uric acid, amino acids, and low-molecular-weight proteins, also known as Fanconi-like syndrome. The underlying molecular basis is largely elusive. We previously reported on Atp6v0a4 knockout (KO) mice, which exhibit severe metabolic acidosis in combination with proximal tubule dysfunction as evidenced by phosphaturia and proteinuria. Here, we show that Rab7, a key regulator of endo-lysosomal trafficking and lysosomal biogenesis, is strongly diminished in proximal tubules of Atp6v0a4 KO mice, while the number of abnormal Ist1-labelled Lamp1-positive vesicles is increased. This is accompanied by the accumulation of autophagosomes, autolysosomes and autophagic substrates. Importantly, correction of metabolic acidosis with bicarbonate therapy resolves proximal tubule dysfunction and trafficking defects in Atp6v0a4 KO mice. Acid-challenged wildtype mice also show trafficking defects with Rab7-downregulation and an increase in Ist1-labeled Lamp1-positive vesicles and develop proximal tubule damage in the long-term. Similar acidosis-induced alterations also occur in human kidney organoids. Altogether, our data provide insights, why patients suffering from severe dRTA may develop a Fanconi-like syndrome, which may contribute to the progression of chronic kidney failure. Translational StatementPatients with renal acidosis caused by impaired proton secretion in the collecting duct (distal renal tubular acidosis - dRTA) sometimes show unexplained symptoms of proximal tubule dysfunction such as proteinuria and phosphaturia. Here, we show that proximal tubules are particularly sensitive to acidosis as evidenced by impaired trafficking, lysosomal damage and accumulation of autophagic substrates. We also show that early treatment of dRTA by alkali supplementation can prevent proximal tubule dysfunction. Because metabolic acidosis represents a well-known risk factor for the progression of chronic kidney disease (CKD), our findings highlight the potential clinical importance of early alkali supplementation to delay disease progression.

molecular biology↗